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Valverde-Villegas JM, Naranjo-Gomez M, Durand M, Rutagwera D, Bedin AS, Kankasa C, Debiesse S, Nagot N, Tuaillon E, Van de Perre P, Molès JP. The CD133 + Stem/Progenitor-Like Cell Subset Is Increased in Human Milk and Peripheral Blood of HIV-Positive Women. Front Cell Infect Microbiol 2020; 10:546189. [PMID: 33102251 PMCID: PMC7546783 DOI: 10.3389/fcimb.2020.546189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022] Open
Abstract
Human milk is a significant source of different CD133+ and/or CD34+ stem/progenitor-like cell subsets in healthy women but their cell distribution and percentages in this compartment of HIV-positive women have not been explored. To date, a decrease of CD34+ hematopoietic stem and progenitor cell frequencies in peripheral blood and bone marrow of HIV-positive patients has been reported. Herein, human milk and peripheral blood samples were collected between day 2–15 post-partum from HIV-positive and HIV-negative women, and cells were stained with stem cell markers and analyzed by flow cytometry. We report that the median percentage of CD45+/highCD34−CD133+ cell subset from milk and blood was significantly higher in HIV-positive than in HIV-negative women. The percentage of CD45dimCD34−CD133+ cell subset from blood was significantly higher in HIV-positive than HIV-negative women. Moreover, percentages of CD45dimCD34+, CD45dimCD34+CD133−, and CD45+highCD34+CD133− cell subsets from blood were significantly lower in HIV-positive than HIV-negative women. The CD133+ stem/progenitor-like cell subsets are increased in early human milk and blood of HIV-positive women and are differentially distributed to CD34+ cell subset frequencies which are decreased in blood.
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Affiliation(s)
- Jacqueline María Valverde-Villegas
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - Mar Naranjo-Gomez
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,IRMB, University of Montpellier, INSERM, CHU Montpellier, Montpellier, France
| | - Mélusine Durand
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - David Rutagwera
- Department of Paediatrics and Child Health, University Teaching Hospital, School of Medicine University of Zambia, Lusaka, Zambia
| | - Anne-Sophie Bedin
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - Chipepo Kankasa
- Department of Paediatrics and Child Health, University Teaching Hospital, School of Medicine University of Zambia, Lusaka, Zambia
| | - Ségolène Debiesse
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
| | - Nicolas Nagot
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, Montpellier, France
| | - Edouard Tuaillon
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, Montpellier, France
| | - Philippe Van de Perre
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France.,CHU Montpellier, Department of Bacteriology-Virology and Department of Medical Information, Montpellier, France
| | - Jean-Pierre Molès
- Pathogenesis and Control of Chronic Infections (PCCI), INSERM, University of Montpellier, Établissement Français du Sang, Montpellier, France
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Shaukat SN, Khan S, Raza A, Khanani R, Ghayaz A, Kazmi SU. Prognostic markers in HIV mono-and co-infected individuals: A study from Karachi-Pakistan. J Infect Public Health 2017; 11:250-254. [PMID: 28844443 DOI: 10.1016/j.jiph.2017.07.027] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Revised: 07/19/2017] [Accepted: 07/31/2017] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Multiple infections are the most common problem among HIV infected individuals. The prognostic impact of these co infections in HIV-population in resource-limited countries like Pakistan has not been fully elucidated. The aim of this study was to assess CD4 and hemoglobin (Hb) levels in patients with HIV mono infection and HIV co-infection with Hepatitis C (HCV), Hepatitis B (HBV) and Mycobacterium tuberculosis (MTB). METHODS A total of 207 HIV positive patients were assessed for CD4 cells count and hemoglobin levels after confirmation of HIV by rapid tests as well as PCR. CD4 counts were performed via flow cytometry whereas hemoglobin levels were performed by Sysmex K-4500 auto-analyzer. RESULTS Out of 207 patients, 22 patients were found to be HIV mono-infected, while 185 patients were HIV positive along with co-infections of MTB or HCV or HBV. We found significant positive correlation between HB levels and CD4 count across the studied group (r=0.30 in HIV mono-infected group, r=0.23 in HIV co-infected group, p<0.05) at baseline. However, majority of the low hemoglobin levels (<8g/dl) and low CD4 count (<200cells/ul) cases were observed particularly in HIV/TB co-infections. CONCLUSION This study documents the prognostic value of hemoglobin assessment in HIV patients. The results indicate that decreasing Hb levels correlate with decreasing CD4 counts. It is emphasizing that Hb measurement may be used as an inexpensive surrogate marker as compared to CD4 analysis for disease progression in HIV patients. In addition, low Hb levels may also indicate presence of under lying co-infections, particularly, with M. tuberculosis (MTB).
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Affiliation(s)
- Sobia N Shaukat
- Dadabhoy Institute of Higher Education, Karachi, Pakistan; Immunology and Infectious Diseases, Research Laboratory, Department of Microbiology, University of Karachi, Pakistan.
| | - Saeed Khan
- Dow University of Health Sciences, Karachi, Pakistan.
| | - Afsheen Raza
- Dadabhoy Institute of Higher Education, Karachi, Pakistan; Clinical Microbiology and Epidemiology, Dadabhoy Institute of Higher Education, Pakistan.
| | - Rafiq Khanani
- Dow University of Health Sciences, Karachi, Pakistan; Department of Pathology, Dow University of Health Sciences, Pakistan.
| | - Azra Ghayaz
- HIV/AIDS Treatment & Care Centre, Civil Hospital, Karachi, Pakistan
| | - Shahana U Kazmi
- Dadabhoy Institute of Higher Education, Karachi, Pakistan; Clinical Microbiology and Immunology-IIDRL And Rector, Dadabhoy Institute of Higher Education, Karachi, Pakistan.
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Voltan R, Rimondi E, Melloni E, Gilli P, Bertolasi V, Casciano F, Rigolin GM, Zauli G, Secchiero P. Metformin combined with sodium dichloroacetate promotes B leukemic cell death by suppressing anti-apoptotic protein Mcl-1. Oncotarget 2017; 7:18965-77. [PMID: 26959881 PMCID: PMC4951344 DOI: 10.18632/oncotarget.7879] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 02/06/2016] [Indexed: 12/28/2022] Open
Abstract
Metformin and the mitochondrial targeting dichloroacetate (DCA) have recently received attention due to their ability to inhibit anaerobic glycolysis, which renders most cancer cells resistant to apoptosis induction. We observed that Metformin alone exhibited a dose-dependent anti-leukemic activity in both B leukemic cell lines and primary B-chronic lymphocytic leukemia (B-CLL) patients' cells and its anti-leukemic activity was enhanced when used in combination with DCA. In order to overcome the problems of poor bioavailability and cellular uptake, which limit DCA efficacy, we have designed and synthetized cocrystals consisting of Metformin and DCA (Met-DCA) at different stoichiometric ratios. Of note, the MetH(2)(++)•2DCA(-) cocrystal exhibited enhanced in vitro anti-leukemic activity, with respect to the treatment with the mix consisting of Metformin plus DCA. In particular, the treatment with the cocrystal MetH(2)(++)•2DCA(-) induced a synergistic apoptotic cell death coupled to a marked down-modulation of the anti-apoptotic Mcl-1 protein. Taken together, our data emphasize that innovative compounds based on Metformin-DCA combination merit to be further evaluated as chemotherapeutic agents for the treatment of B-CLL.
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Affiliation(s)
- Rebecca Voltan
- Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Erika Rimondi
- Department of Life Sciences, University of Trieste, Trieste, Italy
| | - Elisabetta Melloni
- Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Paola Gilli
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
| | - Valerio Bertolasi
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
| | - Fabio Casciano
- Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Gian Matteo Rigolin
- Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy
| | - Giorgio Zauli
- Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Paola Secchiero
- Department of Morphology, Surgery, Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
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Agnoletto C, Brunelli L, Melloni E, Pastorelli R, Casciano F, Rimondi E, Rigolin GM, Cuneo A, Secchiero P, Zauli G. The anti-leukemic activity of sodium dichloroacetate in p53mutated/null cells is mediated by a p53-independent ILF3/p21 pathway. Oncotarget 2016; 6:2385-96. [PMID: 25544776 PMCID: PMC4385858 DOI: 10.18632/oncotarget.2960] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2014] [Accepted: 12/09/2014] [Indexed: 11/25/2022] Open
Abstract
B-chronic lymphocytic leukemia (B-CLL) patients harboring p53 mutations are invariably refractory to therapies based on purine analogues and have limited treatment options and poor survival. Having recently demonstrated that the mitochondria-targeting small molecule sodium dichloroacetate (DCA) exhibits anti-leukemic activity in p53wild-type B-CLL cells, the aim of this study was to evaluate the effect of DCA in p53mutated B-CLL cells and in p53mutated/null leukemic cell lines. DCA exhibited comparable cytotoxicity in p53wild-type and p53mutated B-CLL patient cell cultures, as well as in p53mutated B leukemic cell lines (MAVER, MEC-1, MEC-2). At the molecular level, DCA promoted the transcriptional induction of p21 in all leukemic cell types investigated, including p53null HL-60. By using a proteomic approach, we demonstrated that DCA up-regulated the ILF3 transcription factor, which is a known regulator of p21 expression. The role of the ILF3/p21 axis in mediating the DCA anti-leukemic activity was underscored by knocking-down experiments. Indeed, transfection with ILF3 and p21 siRNAs significantly decreased both the DCA-induced p21 expression and the DCA-mediated cytotoxicity. Taken together, our results emphasize that DCA is a small molecule that merits further evaluation as a therapeutic agent also for p53mutated leukemic cells, by acting through the induction of a p53-independent pathway.
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Affiliation(s)
- Chiara Agnoletto
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Laura Brunelli
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Elisabetta Melloni
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Roberta Pastorelli
- Institute of Pharmacological Researches, IRCCS "Mario Negri", Milano, Italy
| | - Fabio Casciano
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Erika Rimondi
- Department of Life Science, University of Trieste, Trieste, Italy
| | - Gian Matteo Rigolin
- Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy
| | - Antonio Cuneo
- Department of Medical Sciences, University of Ferrara-Arcispedale S. Anna, Ferrara, Italy
| | - Paola Secchiero
- Department of Morphology, Surgery and Experimental Medicine and LTTA Centre, University of Ferrara, Ferrara, Italy
| | - Giorgio Zauli
- Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy
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Gibellini D, Clò A, Morini S, Miserocchi A, Ponti C, Re MC. Effects of human immunodeficiency virus on the erythrocyte and megakaryocyte lineages. World J Virol 2013; 2:91-101. [PMID: 24175233 PMCID: PMC3785048 DOI: 10.5501/wjv.v2.i2.91] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2012] [Revised: 01/07/2013] [Accepted: 01/13/2013] [Indexed: 02/05/2023] Open
Abstract
Anaemia and thrombocytopenia are haematological disorders that can be detected in many human immunodeficiency virus (HIV)-positive patients during the development of HIV infection. The progressive decline of erythrocytes and platelets plays an important role both in HIV disease progression and in the clinical and therapeutic management of HIV-positive patients. HIV-dependent impairment of the megakaryocyte and erythrocyte lineages is multifactorial and particularly affects survival, proliferation and differentiation of bone marrow (BM) CD34+ haematopoietic progenitor cells, the activity of BM stromal cells and the regulation of cytokine networks. In this review, we analyse the major HIV-related mechanisms that are involved in the genesis and development of the anaemia and thrombocytopenia observed in HIV positive patients.
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MacEneaney OJ, Connick E, DeSouza CA. Effects of HIV-1 gp120 and protease inhibitors on apoptotic susceptibility of CD34+ hematopoietic progenitor cells. J Acquir Immune Defic Syndr 2011; 56:e49-50. [PMID: 21233630 PMCID: PMC3038106 DOI: 10.1097/qai.0b013e3181fb1cb3] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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Obienu O, Nwokediuko S. Selected biochemical and hematological abnormalities in Nigerians with human immunodeficiency virus and hepatitis C virus coinfection. Hepat Med 2011; 3:63-8. [PMID: 24367222 PMCID: PMC3846592 DOI: 10.2147/hmer.s21735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Background Liver disease has emerged as a major cause of morbidity and mortality in patients with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection, now that antiretroviral therapy has become more effective and has prolonged life expectancy in HIV-infected patients. The main objectives of this study were to determine the prevalence of HIV/HCV coinfection and the pattern of hematological and biochemical abnormalities associated with such dual infection. Methods In this study, patients with HIV infection (cases) were tested for anti-HCV antibodies. There was a control group made up of apparently healthy individuals who came to hospital for medical examination for various reasons. They also had an anti-HCV antibody test. Those who tested positive for anti-HCV antibodies among the cases and control subjects were further evaluated for hemoglobin concentration, total white cell count, platelet count, and liver function. Results One hundred and eighty HIV-infected patients and 180 control subjects participated in the study. The seroprevalence of anti-HCV antibodies in the HIV-infected patients and control subjects were 6.7% and 4.4%, respectively (P = 0.57). Serum total bilirubin, conjugated bilirubin, and alkaline phosphatase were significantly higher in the HIV/HCV coinfected patients compared with their HCV monoinfected counterparts (P = 0.0396, 0.0001, and 0.0016, respectively). The mean hemoglobin, white cell count, platelet count, and CD4+ T lymphocyte count were significantly lower in the HIV/HCV coinfected patients than the HCV monoinfected control group (P = 0.0082, 0.0133, 0.0031, and 0.0001, respectively). Conclusion The seroprevalence of anti-HCV antibodies in HIV-infected Nigerian patients is 6.7%. Patients with HIV/HCV coinfection have lower blood counts, higher serum bilirubin, and higher serum alkaline phosphatase compared with patients having HCV monoinfection.
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Affiliation(s)
- Olive Obienu
- Gastroenterology Unit, Department of Medicine, University of Nigeria Teaching Hospital Ituku/Ozalla, Enugu, Nigeria
| | - Sylvester Nwokediuko
- Gastroenterology Unit, Department of Medicine, University of Nigeria Teaching Hospital Ituku/Ozalla, Enugu, Nigeria
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Alani A, Vincent O, Adewumi A, Titilope A, Onogu E, Ralph A, Hab C. Plasma folate studies in HIV-positive patients at the Lagos university teaching hospital, Nigeria. Indian J Sex Transm Dis AIDS 2010; 31:99-103. [PMID: 21716795 PMCID: PMC3122594 DOI: 10.4103/0253-7184.74995] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
INTRODUCTION In various studies globally, the prevalence of anemia in persons with HIV infection range from 10 to 20% at initial presentation, and anemia is diagnosed in 70 to 80% of these patients over the course of HIV disease. The etiology of anemia in this group of patients has not been fully established, thus a need to evaluate the role of plasma folate as a possible etiological factor. OBJECTIVE This study was set to determine plasma folate levels in newly diagnosed, treatment naïve, HIV-positive patients, and relate this to other hematological changes. MATERIALS AND METHODS A total of 200 participants were recruited for this study, of which 100 were HIV positive, treatment naive patients who were recruited at the point of registration and 100 were HIV-negative subjects (controls). 5 ml of venous blood was collected and plasma extracted for folic acid estimation by HPLC. A full blood count, CD4 and Viral load were estimated. RESULTS Mean ages for control and study group were 38 ± 2.3 and 32 ± 1.7 years, respectively. Mean plasma folate concentration among the study group (5.04 μg/l) was significantly lower than that for the control group (15.89 μg/l; P = 0.0002). Prevalence of anemia among the study group was 72% (144 of 200), with a mean hemoglobin (Hb) concentration of 9.5 g/dl compared with mean Hb of 13.0 g/dl among the control group (P = 0.002). Plasma folate correlated positively with CD4 cell count (r = 0.304, P<0.05) and inversely with the viral load (r = -0.566; P<0.05). CONCLUSION Plasma folate level is a predictor of anemia in early HIV infections.
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Affiliation(s)
- Akanmu Alani
- Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
| | - Osunkalu Vincent
- Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
| | - Adediran Adewumi
- Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
| | - Adeyemo Titilope
- Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
| | - Ernest Onogu
- Department of Haematology and Blood Transfusion, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
| | - Akinde Ralph
- Department of Morbid Anatomy, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
| | - Coker Hab
- Department of Pharmaceutical Chemistry, College of Medicine, University of Lagos, Surulere, Lagos, Nigeria
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Obirikorang C, Yeboah FA. Blood haemoglobin measurement as a predictive indicator for the progression of HIV/AIDS in resource-limited setting. J Biomed Sci 2009; 16:102. [PMID: 19922646 PMCID: PMC2783029 DOI: 10.1186/1423-0127-16-102] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2009] [Accepted: 11/18/2009] [Indexed: 11/10/2022] Open
Abstract
Background Anaemia is a frequent complication of infection with the human immunodeficiency virus (HIV) and may have multiple causes. The objective of this study was to find out if blood haemoglobin measurement could be used as an indicator for the progression of HIV/AIDS in resource-limited setting. Methods Two hundred and twenty-eight (228) consented People Living with HIV/AIDS (PLWHAs) who were placed in three groups according to their CD4 counts were used in the study. The three groups were those with CD4 counts (1) ≥ 500 mm-3; (2) 200-499 mm-3; and (3) <200 mm-3. One hundred (100) sex, age-matched and healthy HIV-seronegative individuals were used as control subjects. Blood haemoglobin, blood haematocrit, Red cell indices which included Mean Cell Volume, Mean Cell Haemoglobin Concentration and Mean Cell Haemoglobin and CD4 count were analysed in all subjects. Results The mean blood haemoglobin concentrations in those with CD4 counts <200 mm-3, 200-499 mm-3 and ≥ 500 mm-3 (8.83 ± 0.22 g/dl, 10.03 ± 0.31 g/dl and 11.3 ± 0.44 g/dl respectively) were significantly lower when compared with the control group (14.29 ± 0.77 g/dl) (p < 0.0001). The mean blood haematocrit levels in those with CD4 counts <200 mm-3, 200-499 mm-3 and ≥ 500 mm-3 (23.53 ± 0.85%, 28.28 ± 0.77% and 33.54 ± 1.35% respectively) were also significantly lower when compared with the control group (41.15 ± 2.15%) (p < 0.0001). The red cell indices were also lower in the subjects when compared with the control group. Using the Pearson's correlation, there was a significant and positive correlation between the blood haemoglobin level and their CD4 counts (r2 = 0.1755; p < 0.0001). Conclusion Anaemia in People Living with HIV/AIDS, if persistent, is associated with substantially decreased survival. From our analysis, there was a decrease in the blood haemoglobin, levels as the HIV infection progressed and our findings are consistent with those of other studies of anaemia as a prognostic factor in HIV infection. Haemoglobin levels could be measured easily where resources for more sophisticated laboratory markers such as viral load or even CD4 lymphocyte count are not available given that measurement of the CD4 lymphocyte count requires flow cytometry, an expensive technique unavailable in many developing countries. Regular measurements could help to determine which patients are at greatest risk of disease progression, allowing these patients to be identified for closer monitoring or therapeutic intervention.
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Affiliation(s)
- Christian Obirikorang
- Department of Molecular Medicine, School of Medical Sciences, College of Health Sciences, Kwame Nkrumah University of Science and Technology (KNUST), Kumasi, Ghana.
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Mugisha JO, Shafer LA, Van der Paal L, Mayanja BN, Eotu H, Hughes P, Whitworth JAG, Grosskurth H. Anaemia in a rural Ugandan HIV cohort: prevalence at enrolment, incidence, diagnosis and associated factors. Trop Med Int Health 2008; 13:788-94. [PMID: 18384480 DOI: 10.1111/j.1365-3156.2008.02069.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
OBJECTIVES To determine the prevalence and incidence of anaemia in HIV-positive and negative individuals; to identify risk factors for anaemia, prior to the introduction of HAART; and to determine the validity of the clinical diagnosis of anaemia. METHODS Between 1990 and 2003, we followed a rural population based cohort of HIV-infected and uninfected participants. Prevalence and incidence of anaemia were determined clinically and by laboratory measurements. The sensitivity, specificity and predictive values of clinical diagnosis were calculated. RESULTS The prevalence of anaemia at enrolment was 18.9% among HIV-positive and 12.9% among HIV-negative participants (P = 0.065). Incidence of anaemia increased with HIV disease progression, from 103 per 1000 person-years of observation among those with CD4 counts >500 to 289 per 1000 person-years of observation among those with CD4 counts <200. Compared to laboratory diagnosis, the clinical diagnosis of anaemia had a sensitivity of 17.8%, specificity of 96.8%, a positive predictive value of 50.6% and a negative predictive value of 86.4%. Being female, low CD4 cell counts, HIV-positive, wasting syndrome, WHO stage 3 or 4, malaria, fever, pneumonia and oral candidiasis were associated with prevalent anaemia. CONCLUSIONS Anaemia prevalence and incidence were higher among HIV-positive than negative participants. Compared to laboratory diagnosis, clinical detection of anaemia had a low sensitivity. Clinicians working in settings with limited laboratory support must be conscious of the risk of anaemia when managing HIV/AIDS patients, particularly when using antiretroviral drugs which by themselves may cause anaemia as a side effect. We recommend that haemoglobin should be measured before starting ART and monthly for the first three months.
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Gibellini D, Vitone F, Buzzi M, Schiavone P, De Crignis E, Cicola R, Conte R, Ponti C, Re MC. HIV-1 negatively affects the survival/maturation of cord blood CD34(+) hematopoietic progenitor cells differentiated towards megakaryocytic lineage by HIV-1 gp120/CD4 membrane interaction. J Cell Physiol 2007; 210:315-24. [PMID: 17111363 DOI: 10.1002/jcp.20815] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
To investigate the mechanisms involved in the human immunodeficiency virus type 1 (HIV-1)-related thrombocytopenia (TP), human umbilical cord blood (UCB) CD34(+) hematopoietic progenitor cells (HPCs) were challenged with HIV-1(IIIb) and then differentiated by thrombopoietin (TPO) towards megakaryocytic lineage. This study showed that HIV-1, heat-inactivated HIV-1, and HIV-1 recombinant gp120 (rgp120) activated apoptotic process of megakaryocyte (MK) progenitors/precursors and decreased higher ploidy MK cell fraction. All these inhibitory effects on MK survival/maturation and platelets formation were elicited by the interaction between gp120 and CD4 receptor on the cell membrane in the absence of HIV-1 productive infection. In fact, in our experimental conditions, HPCs were resistant to HIV-1 infection and no detectable productive infection was observed. We also evaluated whether the expression of specific cytokines, such as TGF-beta1 and APRIL, involved in the regulation of HPCs and MKs proliferation, was modulated by HIV-1. The specific protein and mRNA detection analysis, during TPO-induced differentiation, demonstrated that HIV-1 upregulates TGF-beta1 and downregulates APRIL expression through the CD4 engagement by gp120. Altogether, these data suggest that survival/differentiation of HPCs committed to MK lineage is negatively affected by HIV-1 gp120/CD4 interaction. This long-term inhibitory effect is also correlated to specific cytokines regulation and it may represent an additional mechanism to explain the TP occurring in HIV-1 patients.
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Affiliation(s)
- Davide Gibellini
- Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy.
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Secchiero P, di Iasio MG, Gonelli A, Barbarotto E, Melloni E, Tiribelli M, Chiaruttini C, Zauli G. Differential gene expression induction by TRAIL in B chronic lymphocytic leukemia (B-CLL) cells showing high versus low levels of Zap-70. J Cell Physiol 2007; 213:229-36. [PMID: 17476690 DOI: 10.1002/jcp.21116] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Among 14 peripheral blood samples obtained from patients affected by B chronic lymphocytic leukemia (B-CLL) at initial stages (Rai 0-1) of the disease, 6 showed intermediate/high levels of Zap-70 while 8 displayed low/absent levels of Zap-70. Although Zap-70(high) and Zap-70(low) B-CLL samples displayed similar levels of surface death receptor TRAIL-R2, recombinant TRAIL induced cytotoxicity only in a subset of Zap-70(low) B-CLL samples while Zap-70(high) were completely resistant to TRAIL. The gene expression profiling was next analyzed in all B-CLL samples treated with either chlorambucil or recombinant TRAIL. While chlorambucil up-regulated the steady-state mRNA levels of known p53 target genes, such as PUMA, Fas/CD95 and MDM2 in all B-CLL samples examined, it significantly down-regulated survivin in Zap-70(low) but not in Zap-70(high). On the other hand, recombinant TRAIL up-regulated the expression of several cytokines (IL-1beta, IL-1alpha, IL-8), which have been involved in promoting B-CLL cell survival. In particular, TRAIL selectively up-regulated IL-1beta in Zap-70(low) B-CLL samples, while it markedly and selectively up-regulated its own mRNA and that of cyclooxigenase-2 (COX-2) in Zap-70(high). Taken together, our findings suggest that a significant expression of Zap-70 modulate the response of B-CLL to TRAIL, which might represents an initial step in the pathogenesis of B-CLL.
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MESH Headings
- Antineoplastic Agents, Alkylating/pharmacology
- Chlorambucil/pharmacology
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- In Vitro Techniques
- Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy
- Leukemia, Lymphocytic, Chronic, B-Cell/enzymology
- Leukemia, Lymphocytic, Chronic, B-Cell/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- RNA, Neoplasm/genetics
- RNA, Neoplasm/metabolism
- Recombinant Proteins/pharmacology
- TNF-Related Apoptosis-Inducing Ligand/pharmacology
- ZAP-70 Protein-Tyrosine Kinase/metabolism
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Affiliation(s)
- Paola Secchiero
- Department of Morphology and Embryology, Human Anatomy Section, University of Ferrara, Ferrara, Italy.
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13
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Gibellini D, Re MC, Vitone F, Rizzo N, Maldini C, La Placa M, Zauli G. Selective up-regulation of functional CXCR4 expression in erythroid cells by HIV-1 Tat protein. Clin Exp Immunol 2003; 131:428-35. [PMID: 12605695 PMCID: PMC1808660 DOI: 10.1046/j.1365-2249.2003.02095.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
CXCR4 is the high affinity receptor for the SDF-1 alpha chemokine and represents the main coreceptor for HIV-1 T-tropic strains. The surface expression of CXCR4 was analysed in CD34+ haematopoietic progenitors, induced to differentiate along the erythroid or granulocytic lineages, in liquid cultures supplemented or not with HIV-1 Tat protein. At concentrations as low as 1-10 ng/ml, synthetic Tat protein significantly increased the surface expression of CXCR4 in erythroid but not in granulocytic cells. The Tat-mediated up-regulation of surface CXCR4 was accompanied by a concomitant increase of CXCR4 mRNA and total CXCR4 protein content in cells developing along the erythroid lineage after 6-10 days of culture. Moreover, addition of SDF-1 alpha (200 ng/ml) induced a significant higher rate of apoptosis in Tat-treated erythroid cells in comparison with control cells. These results demonstrated for the first time a direct positive role in haematopoietic gene regulation of Tat protein, and suggest the possible involvement of Tat in HIV-1-induced anaemia.
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Affiliation(s)
- D Gibellini
- Department of Clinical and Experimental Medicine, Microbiology Section, University of Bologna, Bologna, Italy.
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14
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Nielsen SD, Sørensen TU, Ersbøll AK, Ngo N, Mathiesen L, Nielsen JO, Hansen JE. Decrease in immune activation in HIV-infected patients treated with highly active antiretroviral therapy correlates with the function of hematopoietic progenitor cells and the number of naive CD4+ cells. SCANDINAVIAN JOURNAL OF INFECTIOUS DISEASES 2002; 32:597-603. [PMID: 11200367 DOI: 10.1080/003655400459487] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
This study was conducted to determine the impact of immune activation, cytokine production and apoptosis on the naive CD4+ cell count and the function of hematopoietic progenitor cells during the initial phase of highly active antiretroviral therapy (HAART). Blood samples from 11 HIV-infected patients were collected prior to HAART and after 4 and 12 weeks of therapy. Flow cytometry was used to determine the naive CD4+ count and activated T cells. The cloning efficiency of progenitor cells was determined using a colony-forming cells assay. Finally, apoptosis and cytokine production were determined. During the study period, the naive CD4+ count and the cloning efficiency increased significantly. Immune activation was found in HIV-infected patients and decreased during HAART. The level of immune activation correlated negatively with both the naive CD4+ count and the function of progenitor cells. A negative correlation was found between apoptosis and the naive CD4+ count. Alterations in cytokine production during HAART or correlation between cytokine production and the naive CD4+ count or the cloning efficiency of progenitor cells were not detected. In conclusion, immune activation in HIV-infected patients treated with HAART is inversely correlated with the function of progenitor cells and the naive CD4+ count.
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Affiliation(s)
- S D Nielsen
- Department of Infectious Diseases, Hvidovre Hospital, Denmark
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15
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Nielsen SD, Jeppesen DL, Kolte L, Clark DR, Sørensen TU, Dreves AM, Ersbøll AK, Ryder LP, Valerius NH, Nielsen JO. Impaired progenitor cell function in HIV-negative infants of HIV-positive mothers results in decreased thymic output and low CD4 counts. Blood 2001; 98:398-404. [PMID: 11435309 DOI: 10.1182/blood.v98.2.398] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Hematologic and immunologic functions were examined in 19 HIV-negative infants of HIV-positive mothers and 19 control infants of HIV-negative mothers. Control infants were selected to match for gestational age, weight, and mode of delivery. Cord blood was obtained from all infants and used for flow cytometric determination of lymphocyte subsets, including the naive CD4 count. Furthermore, to determine thymic output, cord blood mononuclear cells were used for determination of T-cell receptor excision circles (TRECs). Evaluation of progenitor cell function was done by means of colony-forming cell assay and fetal thymic organ cultures (FTOCs). Lower naive CD4 counts (459.3 +/- 68.9 vs 1128.9 +/- 146.8 cells/microL, P <.001) and reduced thymic output in infants of HIV-positive mothers were found (frequency of CD4(+) cells with TRECs was 3.6% +/- 0.7% compared with 14.3% +/- 2.2% in controls, P <.001). In combination with lower red blood cell counts in infants of HIV-positive mothers, this finding suggested impairment of progenitor cell function. Indeed, progenitors from infants of HIV-positive mothers had decreased cloning efficiency (15.7% +/- 2.6% vs 55.8% +/- 15.9%, P =.009) and seemed to generate fewer T cells in FTOCs. In conclusion, lower numbers of naive CD4(+) cells and reduced thymic output in HIV-negative infants of HIV-positive mothers may be due to impaired progenitor cell function.
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Affiliation(s)
- S D Nielsen
- Department of Infectious Diseases and Department of Pediatrics, Hvidovre Hospital, Hvidovre, Denmark.
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16
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Affiliation(s)
- R D Semba
- Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
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17
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Kulkosky J, Bouhamdan M, Geist A, Nunnari G, Phinney DG, Pomerantz RJ. Pathogenesis of HIV-1 infection within bone marrow cells. Leuk Lymphoma 2000; 37:497-515. [PMID: 11042510 DOI: 10.3109/10428190009058502] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Mononuclear phagocytic cells and CD4+ T lymphocytes represent the major targets for infection by HIV-1 in vivo. The most severe pathogenic features associated with HIV-1 infection can be attributed to malfunction or premature death of these cells that are of hematopoietic origin. Patients with acquired immunodeficiency syndrome (AIDS), suffer from many hematologic disorders, particularly those persons with long-term infection of HIV-1. These disorders include anemia, lymphocytopenia, thrombocytopenia and neutropenia. The mechanisms that lead to the induction of these disorders are multi-factorial. However, sufficient evidence has accumulated which suggests that HIV-1 infection of cells within the microenvironment of the bone marrow can lead to the induction of hematopoietic deficits. Most studies indicate that marrow-derived hematopoietic stem cells cannot be infected by HIV-1 until they undergo modest differentiation in order to express the appropriate receptors to enable virus entry and subsequent replication. Some cells within the mixed environment of the marrow stroma appear to support HIV-1 replication however. These cells include marrow microvascular endothelial cells, sometimes referred to as blanket cells, stromal fibroblasts, as well as mononuclear phagocytes. Our recent experiments suggest that the HIV-1 accessory protein, Vpr, plays some role in the activation of marrow-derived mononuclear phagocytes which appears to result in premature phagocytosis of non-adherent marrow cells present in the in vitro cultures. This phenomenon could account, in part, for the induction of cytopenias that are typical of individuals infected by HIV-1.
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Affiliation(s)
- J Kulkosky
- Dorrance H. Hamilton Laboratories, Center for Human Virology, Division of Infectious Diseases, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA. 19107, USA
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18
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Voulgaropoulou F, Pontow SE, Ratner L. Productive infection of CD34+-cell-derived megakaryocytes by X4 and R5 HIV-1 isolates. Virology 2000; 269:78-85. [PMID: 10725200 DOI: 10.1006/viro.2000.0193] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
The human immunodeficiency virus (HIV-1) causes various hematopoietic abnormalities, with thrombocytopenia (TP) occurring in 30% of infected individuals. In the present study, we aimed to determine whether HIV-1 in the bone marrow of TP patients can infect primary megakaryocytes in vitro, which may contribute to the development of thrombocytopenia. We amplified the V3 loop of HIV-1 envelope from the bone marrow of TP and non-TP patients and constructed recombinant viruses. We demonstrate that the bone marrow of TP and non-TP patients contained R5 strains, whereas X4 strains were present only in the bone marrow of TP patients. Furthermore, HIV-1 from the bone marrow of TP and non-TP patients infected megakaryocytes to similar levels, suggesting that the V3 loop of HIV-1 may not contain the viral determinants of HIV-associated TP. Chemokine receptor analysis determined that CD34+-cell-derived megakaryocytes express CD4, CXCR4, and CCR5 and are productively infected by both X4 and R5 HIV-1 isolates. Finally, we showed that CD34+-cell-derived megakaryocytes express the chemokine receptor CCR3.
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Affiliation(s)
- F Voulgaropoulou
- Departments of Medicine, Pathology, and Molecular Microbiology, Washington University, St. Louis, MO 63110, USA
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19
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Hariharan D, Li Y, Campbell DE, Douglas SD, Starr SE, Ho W. Human immunodeficiency virus infection of human placental cord blood CD34+AC133+ stem cells and their progeny. AIDS Res Hum Retroviruses 1999; 15:1545-52. [PMID: 10580405 DOI: 10.1089/088922299309838] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The AC133 is a novel antigen selectively expressed on primitive CD34bright stem cells and is a valuable marker for the selection of long-term culture-initiating cells (LTC-ICs) and severe combined immunodeficiency (SCID)-repopulating cells. Human placental cord blood (HPCB) is a rich source of CD34+AC133+ cells. Since AC133 antibody is likely to be used as an alternative to CD34 for the selection of stem cells in transplant and gene therapy situations, we examined the susceptibility of HPCB-isolated CD34+AC133+ stem cells to infection with free and cell-associated HIV-1 in vitro. Freshly isolated HPCB CD34+AC133+ stem cells were not susceptible to HIV-1 infection as determined by PCR and reverse transcriptase assays. Inoculation with HIV-1 did not affect the viability and clonogenic ability of HPCB CD34+AC133+ cells. Although the highly purified HPCB CD34+AC133+ stem cells contained mRNA for CD4 and CXCR4 receptors, CD4 and CXCR4 proteins were not expressed on these cells. Similarly, CCR5 protein, the major macrophage-tropic HIV-1 coreceptor, was not expressed in freshly isolated HPCB CD34+AC133+ stem cells, although the transcript for CCR5 was identified in these cells. Expression of CD4, CXCR4, and CCR5 receptor proteins on the progeny derived from HPCB CD34+AC133+ stem cells was detected and correlated with susceptibility to HIV-1 infection in vitro. These findings suggest that freshly isolated HPCB CD34+AC133+ stem cells are not susceptible to HIV-1 infection and may not be a viral reservoir. These data have important implications for the use of AC133 antibody as a means of enriching for primitive hematopoietic stem cells from placental cord blood and in the design of stem cell or progenitor cell-based gene therapeutic strategies for perinatal HIV-1 infection.
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Affiliation(s)
- D Hariharan
- Department of Pediatrics, University of Pennsylvania Medical School, Philadelphia 19104, USA
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20
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Affiliation(s)
- D R Clark
- Department of Clinical Viro-Immunology, University of Amsterdam, The Netherlands
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21
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Haase AT. Population biology of HIV-1 infection: viral and CD4+ T cell demographics and dynamics in lymphatic tissues. Annu Rev Immunol 1999; 17:625-56. [PMID: 10358770 DOI: 10.1146/annurev.immunol.17.1.625] [Citation(s) in RCA: 381] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Human immunodeficiency virus-1 (HIV-1) is usually transmitted through sexual contact and in the very early stages of infection establishes a persistent infection in lymphatic tissues (LT). Virus is produced and stored at this site in a dynamic process that slowly depletes the immune system of CD4+ T cells, setting the stage for AIDS. In this review, I describe the changes in viral and CD4+ T cell populations in LT over the course of infection and after treatment. I present recent evidence that productively infected CD4+ T cells play an important role in establishing persistent infection from the onset, and that the LT are the major reservoir where virus is produced and stored on follicular dendritic cells (FDCs). I discuss the methods used to define the size of viral and CD4+ T cell populations in LT and the nature of virus-host cell interactions in vivo. These experimental approaches have identified populations of latently and chronically infected cells in which virus can elude host defenses, perpetuate infection, and escape eradication by highly active antiretroviral treatment (HAART). I discuss the dramatic impact of HAART on suppressing virus production, reducing the pool of stored virus, and restoring CD4+ T cell populations. I discuss the contributions of thymopoiesis and other renewal mechanisms, lymphatic homeostasis and trafficking to these changes in CD4+ T cell populations in LT, and conclude with a model of immune depletion and repopulation based on the limited regenerative capacity of the adult and the uncompensated losses of productively infected cells that treatment stems. The prediction of this model is that immune regeneration will be slow, variable, and partial. It is nonetheless encouraging to know that even in late stages of infection, control of active replication of HIV-1 provides an opportunity for the immune system to recover from the injuries inflicted by infection.
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Affiliation(s)
- A T Haase
- Department of Microbiology, University of Minnesota, Minneapolis 55455, USA.
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22
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Mattapallil JJ, Smit-McBride Z, Dandekar S. Gastrointestinal epithelium is an early extrathymic site for increased prevalence of CD34(+) progenitor cells in contrast to the thymus during primary simian immunodeficiency virus infection. J Virol 1999; 73:4518-23. [PMID: 10196359 PMCID: PMC104348 DOI: 10.1128/jvi.73.5.4518-4523.1999] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
The objective of this study was to determine the effects of primary simian immunodeficiency virus (SIV) infection on the prevalence and phenotype of progenitor cells present in the gastrointestinal epithelia of SIV-infected rhesus macaques, a primate model for human immunodeficiency virus pathogenesis. The gastrointestinal epithelium was residence to progenitor cells expressing CD34 antigen, a subset of which also coexpressed Thy-1 and c-kit receptors, suggesting that the CD34(+) population in the intestine comprised a subpopulation of primitive precursors. Following experimental SIVmac251 infection, an early increase in the proportions of CD34(+) Thy-1(+) and CD34(+) c-kit+ progenitor cells was observed in the gastrointestinal epithelium. In contrast, the proportion of CD34(+) cells in the thymus declined during primary SIV infection, which was characterized by a decrease in the frequency of CD34(+) Thy-1(+) progenitor cells. A severe depletion in the frequency of CD4-committed CD34(+) progenitors was observed in the gastrointestinal epithelium 2 weeks after SIV infection which persisted even 4 weeks after infection. A coincident increase in the frequency of CD8- committed CD34(+) progenitor cells was observed during primary SIV infection. These results indicate that in contrast to the primary lymphoid organs such as the thymus, the gastrointestinal epithelium may be an early extrathymic site for the increased prevalence of both primitive and committed CD34(+) progenitor cells. The gastrointestinal epithelium may potentially play an important role in maintaining T-cell homeostasis in the intestinal mucosa during primary SIV infection.
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Affiliation(s)
- J J Mattapallil
- Department of Internal Medicine, Division of Infectious Diseases, School of Medicine, University of California Davis, Davis, California, USA
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23
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Voulgaropoulou F, Tan B, Soares M, Hahn B, Ratner L. Distinct human immunodeficiency virus strains in the bone marrow are associated with the development of thrombocytopenia. J Virol 1999; 73:3497-504. [PMID: 10074209 PMCID: PMC104119 DOI: 10.1128/jvi.73.4.3497-3504.1999] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
We analyzed bone marrow and blood from human immunodeficiency virus type 1 (HIV-1)-infected individuals and described the HIV-1 quasispecies in these cellular compartments. HIV-1 isolates from the bone marrow of thrombocytopenic patients contained distinct amino acids in the V3 loop and infected T-cell lines, implicating this virus in the development of thrombocytopenia.
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Affiliation(s)
- F Voulgaropoulou
- Departments of Medicine, Washington University, St. Louis, Missouri 63110, USA
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24
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Rubinstein DB, Leblanc P, Wright DG, Guillaume T, Strotchevoi A, Boosalis M. Anti-CD34+ Fabs generated against hematopoietic stem cells in HIV-derived combinatorial immunoglobulin library suggest antigen-selected autoantibodies. Mol Immunol 1998; 35:955-64. [PMID: 9881691 DOI: 10.1016/s0161-5890(98)00075-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Bone marrow suppression associated with HIV infection does not appear to be solely due to direct viral cytopathic effects. Autoantibodies may play a role in myelosuppression, however it is unclear whether autoantibodies produced in HIV infection represent a primary pathogenic process or merely reflect polyclonal B cell activation. To address these questions, we generated combinatorial immunoglobulin libraries using the pComb3 phagemid from an HIV+ individual with evidence of circulating autoantibodies. From one library, three anti-CD34 Fabs were identified using fresh CD34+ cells as antigenic targets by a method of phage subtraction. The anti-CD34 Fabs are specific by immunoblotting and Elisa and are of high affinity, with calculated Kds in the range of 10(-7) -10(-8) M. Nucleic acid sequencing revealed all three to be of the VH3 family and to have lambda light chains with some gene segments expressing little somatic mutation, while other segments were somatically mutated in patterns suggestive of antigen selection. These findings indicate that (1) A subset of HIV-associated anti-CD34 autoantibodies are monospecific and antigen-selected and are not merely a consequence of polyclonal B cell activation and elevated Ig levels in HIV. Autoreactivity in HIV therefore includes both polyspecific, low affinity antibodies as well as monospecific antigen-selected high affinity antibodies. (2) Although bone marrow suppression in HIV is likely to be multifactorial, autoantibodies to hematopoietic stem cells may contribute to its pathogenesis. (3) Library sampling of VH gene family rearrangements shows no evidence for under-representation of the VH3 family in the immune dysregulation of HIV infection. Phage subtraction is corroborated to be an effective means of identifying, cloning, and characterizing antibodies to hematopoietic differentiation antigens.
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Affiliation(s)
- D B Rubinstein
- Section of Hematology/Oncology, Boston University School of Medicine, MA 02118, USA.
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25
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26
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27
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Dobmeyer TS, Dobmeyer JM, Klein SA, Wesch D, Wagner S, Helm EB, Hoelzer D, Rossol R, Kabelitz D. Mechanism of gamma sigma T-cell-mediated inhibition of stem cell differentiation in vitro: possible relevance for myelosuppression in HIV-infected individuals. Cell Immunol 1998; 184:26-36. [PMID: 9626332 DOI: 10.1006/cimm.1998.1257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We investigated whether gamma delta T cells contribute to the suppression of myelopoiesis in HIV infection. Freshly isolated gamma delta T cells from HIV seropositive patients suppressed CFU-GM growth in vitro. Preactivation of gamma delta T cells with IL-2 and/or IL-15 further reduced the number of CFU-GM. Natural killer cells and to a lower extent CD4+ and CD8+ cells also inhibited CFU-GM growth. In contrast to gamma delta T cells, this effect was not dependent on IL-15 or IL-2 preactivation. Moreover, no enhanced inhibitory effect of CD56+ and CD4+ cells was observed in HIV+ subjects compared to HIV- donors. The myelosuppressive effect of supernatants of gamma delta T cells could be inhibited by antibodies against IFN-gamma or TNF-alpha. Accordingly, we found increased numbers of TNF-alpha or IFN-gamma-secreting CD8+ gamma delta T cells in HIV+ patients. We conclude that the increased fraction of activated gamma delta T cells producing myelosuppressive cytokines might contribute to the dyshematopoiesis frequently observed in HIV-infected individuals.
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Affiliation(s)
- T S Dobmeyer
- Paul-Ehrlich-Institute, Department of Immunology, Langen, Germany
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28
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Epidemiology of Anemia in Human Immunodeficiency Virus (HIV)-Infected Persons: Results From the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project. Blood 1998. [DOI: 10.1182/blood.v91.1.301.301_301_308] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
To study the incidence of, the factors associated with, and the effect on survival of anemia in human immunodeficiency virus (HIV)-infected persons, we analyzed data from the longitudinal medical record reviews of 32,867 HIV-infected persons who received medical care from January 1990 through August 1996 in clinics, hospitals, and private medical practices in nine United States cities. We calculated the 1-year incidence of anemia (a hemoglobin level of <10 g/dL or a physician diagnosis of anemia); the adjusted odds ratios showing excess risk of anemia associated with demographic factors, prescribed therapies, and concurrent diseases; the risk of death for patients who developed anemia compared with risk for patients who did not develop anemia; and, of patients who did develop anemia, the risk of death for those who did not recover from anemia compared with the risk for those who did recover. The 1-year incidence of anemia was 36.9% for persons with one or more acquired immunodeficiency syndrome (AIDS)-defining opportunistic illnesses (clinical AIDS), 12.1% for patients with a CD4 count of less than 200 cells/μm or CD4 percentage of <14 but not clinical AIDS (immunologic AIDS), and 3.2% for persons without clinical or immunologic AIDS. Of anemia diagnoses, 22% were identified by physicians as drug related. Incidence of anemia was associated with clinical AIDS, immunologic AIDS, neutropenia, thrombocytopenia, bacterial septicemia, black race, female sex, prescription of zidovudine, fluconazole, and ganciclovir, and lack of prescription of trimethoprim-sulfamethoxazole. The increased risk of death associated with anemia differed by first CD4 count: for patients with a CD4 count of ≥200 cells/μL at the beginning of the survival analysis, the risk of death was 148% (99% confidence interval [CI], 114 to 188) greater for those who developed anemia; for patients whose first CD4 count was <200 cells/μL, the risk of death was 56% (99% CI, 43 to 71) greater for those in whom anemia developed. For persons in whom anemia developed, the risk of death was 170% (99% CI, 132 to 203) greater for persons who did not recover from anemia compared with those who did recover. Anemia is a frequent complication of HIV infection, and its incidence is associated with progression of HIV disease, prescription of certain chemotherapeutics, black race, and female sex. Anemia, particularly anemia that does not resolve, is associated with shorter survival of HIV-infected patients.
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29
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Wolthers KC, Schuitemaker H, Miedema F. Rapid CD4+ T-cell turnover in HIV-1 infection: a paradigm revisited. IMMUNOLOGY TODAY 1998; 19:44-8. [PMID: 9465488 DOI: 10.1016/s0167-5699(97)01188-2] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- K C Wolthers
- Dept of Clinical Viro-Immunology, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands.
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30
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Epidemiology of Anemia in Human Immunodeficiency Virus (HIV)-Infected Persons: Results From the Multistate Adult and Adolescent Spectrum of HIV Disease Surveillance Project. Blood 1998. [DOI: 10.1182/blood.v91.1.301] [Citation(s) in RCA: 247] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
To study the incidence of, the factors associated with, and the effect on survival of anemia in human immunodeficiency virus (HIV)-infected persons, we analyzed data from the longitudinal medical record reviews of 32,867 HIV-infected persons who received medical care from January 1990 through August 1996 in clinics, hospitals, and private medical practices in nine United States cities. We calculated the 1-year incidence of anemia (a hemoglobin level of <10 g/dL or a physician diagnosis of anemia); the adjusted odds ratios showing excess risk of anemia associated with demographic factors, prescribed therapies, and concurrent diseases; the risk of death for patients who developed anemia compared with risk for patients who did not develop anemia; and, of patients who did develop anemia, the risk of death for those who did not recover from anemia compared with the risk for those who did recover. The 1-year incidence of anemia was 36.9% for persons with one or more acquired immunodeficiency syndrome (AIDS)-defining opportunistic illnesses (clinical AIDS), 12.1% for patients with a CD4 count of less than 200 cells/μm or CD4 percentage of <14 but not clinical AIDS (immunologic AIDS), and 3.2% for persons without clinical or immunologic AIDS. Of anemia diagnoses, 22% were identified by physicians as drug related. Incidence of anemia was associated with clinical AIDS, immunologic AIDS, neutropenia, thrombocytopenia, bacterial septicemia, black race, female sex, prescription of zidovudine, fluconazole, and ganciclovir, and lack of prescription of trimethoprim-sulfamethoxazole. The increased risk of death associated with anemia differed by first CD4 count: for patients with a CD4 count of ≥200 cells/μL at the beginning of the survival analysis, the risk of death was 148% (99% confidence interval [CI], 114 to 188) greater for those who developed anemia; for patients whose first CD4 count was <200 cells/μL, the risk of death was 56% (99% CI, 43 to 71) greater for those in whom anemia developed. For persons in whom anemia developed, the risk of death was 170% (99% CI, 132 to 203) greater for persons who did not recover from anemia compared with those who did recover. Anemia is a frequent complication of HIV infection, and its incidence is associated with progression of HIV disease, prescription of certain chemotherapeutics, black race, and female sex. Anemia, particularly anemia that does not resolve, is associated with shorter survival of HIV-infected patients.
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Infection of Human Marrow Stroma by Human Immunodeficiency Virus-1 (HIV-1) Is Both Required and Sufficient for HIV-1–Induced Hematopoietic Suppression In Vitro: Demonstration by Gene Modification of Primary Human Stroma. Blood 1997. [DOI: 10.1182/blood.v90.5.1787] [Citation(s) in RCA: 76] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractPatients with human immunodeficiency virus-1 (HIV-1) infection often present with bone marrow (BM) failure that may affect all hematopoietic lineages. It is presently unclear whether this failure reflects a direct viral impairment of the CD34+ hematopoietic progenitor cells or whether the virus affects the BM microenvironment. To study the effects of HIV-1 on the BM microenvironment, we examined the stromal cell monolayers in long-term BM culture (LTBMC), which are the in vitro equivalent of the hematopoietic microenvironment. We assessed the hematopoietic support function (HSF ) of human stromal layers by determining the cellular proliferation and colony-forming ability of hematopoietic progenitors from BM cells grown on the stromal layers. We show that the HSF is reduced by in vitro infection of the human stromal cell layer by a monocytotropic isolate of HIV-1 (JR-FL). There is no loss of HSF when the stromal cell layer is resistant to HIV-1 replication, either using murine stromal cell layers that are innately resistant to HIV-1 infection or using human stromal cells genetically modified to express a gene that inhibits HIV-1 replication (an RRE decoy). Decreased HSF was seen using either human or murine hematopoietic cells, if the stromal cells were human cells that were susceptible to HIV-1 infection. These in vitro studies implicate HIV-1 replication in the stroma as the essential component causing decreased hematopoietic cell production in HIV-1 infection.
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Hematopoietic Potential and Retroviral Transduction of CD34+Thy-1+ Peripheral Blood Stem Cells From Asymptomatic Human Immunodeficiency Virus Type-1–Infected Individuals Mobilized With Granulocyte Colony-Stimulating Factor. Blood 1997. [DOI: 10.1182/blood.v89.12.4299] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractThe potential of hematopoietic stem cells (HSCs) from human immunodeficiency virus type-1 (HIV-1)–infected individuals, eg, self-renewal and multilineage differentiative capacity, might be perturbed due to the underlying disease. In this study, we assessed the HSC activity in the CD34+Thy-1+ cell population of peripheral blood stem cells (PBSCs) of three asymptomatic HIV-1–infected individuals after granulocyte colony-stimulating factor (G-CSF; 10 μg/kg/d) mobilization. On day 4 of G-CSF treatment, 0.8% to 1% of the total blood mononuclear cells were CD34+. Leukapheresis followed by a two-step cell isolation process yielded a CD34+Thy-1+ cell population of high purity (76% to 92% CD34+Thy-1+ cells). This cell population showed no evidence of HIV-1–containing cells based on a semiquantitative HIV-1 DNA polymerase chain reaction. Furthermore, the purified cells showed normal hematopoietic potential in in vitro clonogenic assays. Successful gene transfer into committed progenitor cells (colony-forming units-cells) and more primitive stem/progenitor cells (long-term culture colony-forming cells) could be shown after amphotropic retroviral transduction. These data provide evidence that the CD34+Thy-1+ stem cell compartment can be mobilized and enriched in early stage HIV-1–infected patients. Furthermore, successful transduction of this cell population as a prerequisite for stem cell-based clinical gene therapy protocols was demonstrated.
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Expression of the Human Immunodeficiency Virus Type-1 Coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ Hematopoietic Progenitor Cells. Blood 1997. [DOI: 10.1182/blood.v89.10.3522] [Citation(s) in RCA: 101] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
AbstractCD34+ hematopoietic progenitor cells were assessed for mRNA expression of the human immunodeficiency virus type-1 (HIV-1) coreceptors CXCR-4, also termed fusin or LESTR, and CKR-5, also called CC-CKR-5 or CCR-5. The CD34+ cells were obtained from leukapheresis products of 17 patients after granulocyte colony-stimulating factor–supported cytotoxic chemotherapy. Using a two-step enrichment procedure including immunomagnetic bead separation and fluorescence-activated cell sorting, the CD34+ cells had a median purity of 99.8%. Assessing 9 CD34+ cell samples by polymerase chain reaction after reverse transcription (RT-PCR), CXCR-4 mRNA was found in all samples, whereas CKR-5 mRNA was only present in 3 samples, even though a nested PCR was used. Eight additional CD34+ cell samples were sorted according to CD4 expression. Based on a three-color immunofluorescence analysis, the mean relative fluorescence intensity of HLA-DR was smaller on CD34+/CD4+ cells in comparison with CD34+/CD4− cells. CXCR-4 mRNA was found in 5 of 8 CD34+/CD4+ samples and in 7 of 8 CD34+/CD4− samples, whereas CKR-5 mRNA was detected in 2 CD34+/CD4+ samples and in 1 CD34+/CD4− cell sample. Looking at the total number of CD34+ cell samples examined, the proportion of specimens containing CXCR-4 mRNA was 84% in comparison with 24% of specimens positive for CKR-5 mRNA. These data suggest that CD34+/CD4+ hematopoietic progenitor cells, including true stem cell candidates, could be susceptible to HIV-1 infection. Considering the relatively low incidence of CD34+ cell samples containing CKR-5 mRNA, CD34+/CD4+ cells appear to be particularly prone for HIV-1 infection via the CXCR-4 coreceptor. Because this chemokine receptor allows T-cell–tropic HIV-1 strains to infect cells, CD34+ cells expressing CD4 and CXCR-4 might be infected by HIV-1 during later stages of the disease, following a viral phenotype switch from macrophage- to T-cell–tropic HIV-1 strains.
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34
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Expression of the Human Immunodeficiency Virus Type-1 Coreceptors CXCR-4 (fusin, LESTR) and CKR-5 in CD34+ Hematopoietic Progenitor Cells. Blood 1997. [DOI: 10.1182/blood.v89.10.3522.3522_3522_3528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
CD34+ hematopoietic progenitor cells were assessed for mRNA expression of the human immunodeficiency virus type-1 (HIV-1) coreceptors CXCR-4, also termed fusin or LESTR, and CKR-5, also called CC-CKR-5 or CCR-5. The CD34+ cells were obtained from leukapheresis products of 17 patients after granulocyte colony-stimulating factor–supported cytotoxic chemotherapy. Using a two-step enrichment procedure including immunomagnetic bead separation and fluorescence-activated cell sorting, the CD34+ cells had a median purity of 99.8%. Assessing 9 CD34+ cell samples by polymerase chain reaction after reverse transcription (RT-PCR), CXCR-4 mRNA was found in all samples, whereas CKR-5 mRNA was only present in 3 samples, even though a nested PCR was used. Eight additional CD34+ cell samples were sorted according to CD4 expression. Based on a three-color immunofluorescence analysis, the mean relative fluorescence intensity of HLA-DR was smaller on CD34+/CD4+ cells in comparison with CD34+/CD4− cells. CXCR-4 mRNA was found in 5 of 8 CD34+/CD4+ samples and in 7 of 8 CD34+/CD4− samples, whereas CKR-5 mRNA was detected in 2 CD34+/CD4+ samples and in 1 CD34+/CD4− cell sample. Looking at the total number of CD34+ cell samples examined, the proportion of specimens containing CXCR-4 mRNA was 84% in comparison with 24% of specimens positive for CKR-5 mRNA. These data suggest that CD34+/CD4+ hematopoietic progenitor cells, including true stem cell candidates, could be susceptible to HIV-1 infection. Considering the relatively low incidence of CD34+ cell samples containing CKR-5 mRNA, CD34+/CD4+ cells appear to be particularly prone for HIV-1 infection via the CXCR-4 coreceptor. Because this chemokine receptor allows T-cell–tropic HIV-1 strains to infect cells, CD34+ cells expressing CD4 and CXCR-4 might be infected by HIV-1 during later stages of the disease, following a viral phenotype switch from macrophage- to T-cell–tropic HIV-1 strains.
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35
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Mondal D, Agrawal KC. Effect of HIV type 1 Tat protein on butyric acid-induced differentiation in a hematopoietic progenitor cell line. AIDS Res Hum Retroviruses 1996; 12:1529-36. [PMID: 8911578 DOI: 10.1089/aid.1996.12.1529] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
The trans-activator protein (Tat) of HIV-1 plays an important role in viral pathogenesis. Since Tat has been shown to alter expression of a number of host cellular genes, we have investigated the role of Tat in modulating gene expression and differentiation in hematopoietic progenitor cells. Tat protein was introduced in K562 cells, a human hematopoietic progenitor cell line, by either scrape-loading onto HeLa (HL)-tat cells or direct electroporation of an affinity-purified glutathione S-transferase (GST)-Tat fusion protein. Under these conditions, butyric acid-induced hemoglobin production in K562 cells was suppressed by 65 and 52%, respectively. However, coculturing with wild-type HeLa cells or electroporation with the control GST protein did not decrease hemoglobin production. To confirm the presence of bioactive Tat protein within K562 cells, the cells were transiently transfected with a pHIV/LTR-CAT prior to the introduction of Tat. A 30- to 40-fold induction in CAT gene expression was observed in the transfected K562 cells, which were either cocultured with HL-tat or were electroporated with GST-Tat. Simultaneous transient transfection of K562 cells with a TAR expression plasmid, to compete for the availability of Tat protein, significantly downregulated the HIV LTR trans-activation by Tat. In addition, overexpression of the TAR RNAs in K562 cells was able to downregulate the suppressive effect of Tat on butyric acid-induced differentiation. RT-PCR analysis of the total RNAs isolated from these cells demonstrated that Tat protein suppressed the butyric acid-induced gamma-globin gene expression by an average of 54% without affecting the level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNAs. These data indicate that the viral Tat protein plays a significant role in abrogating erythroid differentiation in K562 cells.
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Affiliation(s)
- D Mondal
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA
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36
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Zauli G, Vitale M, Gibellini D, Capitani S. Inhibition of purified CD34+ hematopoietic progenitor cells by human immunodeficiency virus 1 or gp120 mediated by endogenous transforming growth factor beta 1. J Exp Med 1996; 183:99-108. [PMID: 8551249 PMCID: PMC2192418 DOI: 10.1084/jem.183.1.99] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Human CD34+ hematopoietic progenitor cells, stringently purified from the peripheral blood of 20 normal donors, showed an impaired survival and clonogenic capacity after exposure to either heat-inactivated human immunodeficiency virus (HIV) 1 (strain IIIB) or cross-linked envelope gp120. Cell cycle analysis, performed at different times in serum-free liquid culture, showed an accumulation in G0/G1 in HIV-1- or gp120-treated cells and a progressive increase of cells with subdiploid DNA content, characteristic of apoptosis. In blocking experiments with anti-transforming growth factor (TGF) beta 1 neutralizing serum or TGF-beta 1 oligonucleotides, we demonstrated that the HIV-1- or gp120-mediated suppression of CD34+ cell growth was almost entirely due to an upregulation of endogenous TGF-beta 1 produced by purified hematopoietic progenitors. Moreover, by using a sensitive assay on the CCL64 cell line, increased levels of bioactive TGF-beta 1 were recovered in the culture supernatant of HIV-1/gp120-treated CD34+ cells. Anti-TGF-beta 1 neutralizing serum or TGF-beta 1 oligonucleotides were also effective in inducing a significant increase of the plating efficiency of CD34+ cells, purified from the peripheral blood of three HIV-1-seropositive individuals, suggesting that a similar mechanism may be also operative in vivo. The relevance of these findings to a better understanding of the pathogenesis of HIV-1-related cytopenias is discussed.
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Affiliation(s)
- G Zauli
- Institute of Human Anatomy, University of Ferrara, Italy
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37
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Davis BR, Zauli G. Effect of human immunodeficiency virus infection on haematopoiesis. BAILLIERE'S CLINICAL HAEMATOLOGY 1995; 8:113-30. [PMID: 7545035 DOI: 10.1016/s0950-3536(05)80234-3] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
The pathogenesis of peripheral blood cytopenias in AIDS patients is clearly multifactorial. Among the various contributing mechanisms, those involving a direct role of HIV-1 have been actively investigated in the past few years. It has now been convincingly demonstrated that HIV can impair the survival/proliferative capacity of purified haematopoietic progenitor cells. Although a subset of haematopoietic progenitor cells are perhaps susceptible to HIV-1 infection, both in vitro and in vivo, the suppressive effect does not require either active or latent infection and is probably mediated by the interaction of viral or virus-associated proteins with the cell membrane of haematopoietic progenitor cells. Both the viral load and the biological characteristics of the virus play an important role in suppression, since different isolates displayed different inhibitory activity. Haematosuppression is not a specific property of monocytotropic versus lymphocytotropic or low-replicating versus high-replicating isolates, and it will be important to exactly establish which viral component is crucial to suppression of haematopoietic progenitor cells. Since the haematopoietic stem cell is the common progenitor to both the myeloid and lymphoid lineages, the capacity of HIV to impair the growth of early haematopoietic progenitor cells could contribute not only to the frequent occurrence of anaemia, granulocytopenia and thrombocytopenia in AIDS patients, but also to the inability of the bone marrow to reconstitute a functional pool of mature CD4+ T-cells. It is also possible that haematopoietic progenitor cells committed to the T-lymphoid lineage are impaired by HIV in their differential pathway within the thymus (Bonyhadi et al, 1993). Infection of megakaryocytes could result in underproduction of platelets and possibly represents a major pathogenetic mechanism of HIV-related thrombocytopenia. Infection of monocytes and T-lymphocytes leads in vitro and probably also in vivo to deranged cytokine production. In the first stages of the disease, increased cytokine production, consequent to a chronic immune activation, is probably responsible for the myelodysplastic/hyperplastic alterations observed at the bone marrow level. In more advanced stages of the disease, the general decline in immune function, the consequent imbalance in cytokine production, and the increase in viral burden, may contribute to dysregulated haematopoiesis and peripheral blood cytopenias.
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Affiliation(s)
- B R Davis
- Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA
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38
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Yu M, Leavitt MC, Maruyama M, Yamada O, Young D, Ho AD, Wong-Staal F. Intracellular immunization of human fetal cord blood stem/progenitor cells with a ribozyme against human immunodeficiency virus type 1. Proc Natl Acad Sci U S A 1995; 92:699-703. [PMID: 7531339 PMCID: PMC42687 DOI: 10.1073/pnas.92.3.699] [Citation(s) in RCA: 80] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
Successful treatment of human immunodeficiency virus infection may ultimately require targeting of hematopoietic stem cells. Here we used retroviral vectors carrying the ribozyme gene to transduce CD34+ cells from human fetal cord blood. Transduction and ribozyme expression had no apparent adverse effect on cell differentiation and/or proliferation. The macrophage-like cells, differentiated from the stem/progenitor cells in vitro, expressed the ribozyme gene and resisted infection by a macrophage tropic human immunodeficiency virus type 1. These results suggest the feasibility of stem cell gene therapy for human immunodeficiency virus-infected patients.
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Affiliation(s)
- M Yu
- Department of Medicine, University of California, San Diego, La Jolla 92093-0665
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39
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The Hematopathology of HIV-1 Disease: Experimental Analysis in Vivo. HUMAN HEMATOPOIESIS IN SCID MICE 1995. [DOI: 10.1007/978-3-662-22008-5_7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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40
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Nagasaki M, Harada T, Torii I, Nakano A, Furuya H, Tanaka J, Hirai K, Morikawa S. An autopsy case of acquired immune deficiency syndrome (AIDS) with preceding aplastic anemia. Pathol Int 1994; 44:850-6. [PMID: 7866568 DOI: 10.1111/j.1440-1827.1994.tb01683.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
A case of acquired immunodeficiency syndrome (AIDS) with preceding aplastic anemia is reported. The patient was a 36 year old female who had been diagnosed as having aplastic anemia 10 years before and thereafter had received multiple transfusions. Human immunodeficiency virus (HIV)-seropositivity was revealed 10 months prior to her death, but no particular clinical signs indicating HIV infection, pre-AIDS or onset of AIDS were recognized before serological diagnosis, although the slow progression of leukopenia was noted along with thrombocytopenia. Her general condition deteriorated during the last 10 months accompanied by an acute decrease in the CD4/CD8 ratio. Autopsy revealed full-blown AIDS: systemic aspergillosis, progressive multifocal leukoencephalopathy, Epstein-Barr virus-related B cell lymphoma arising in the diaphragm and severe lymphocyte depletion in the lymph nodes and spleen. Markedly hypoplastic bone marrow was considered to be primarily attributable to the aplastic anemia but the affection of AIDS was not excluded. The possible transmission route of HIV and the effect of the preceding aplastic anemia on the infection and clinical course of AIDS are discussed.
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Affiliation(s)
- M Nagasaki
- Department of Pathology, Shimane Medical University, Izumo, Japan
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41
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Lazzarotto T, Furlini G, Re MC, Ramazzotti E, Campisi B, Landini MP. Human cytomegalovirus replication correlates with differentiation in a hematopoietic progenitor cell line and can be modulated by HIV-1. Arch Virol 1994; 135:13-28. [PMID: 7515223 DOI: 10.1007/bf01309762] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Human cytomegalovirus (HCMV) infection of a CD34+ hematopoietic progenitor cell line (TF1) was studied before and after TPA differentiation. TF1 cells were found to be infected but the virus does not replicate, while differentiated TF1 cells can be infected and allow HCMV complete replication. In the same system we studied the interaction between HCMV and HIV and found that while contact between HIV gp 120 and the HCMV-infected cell has an inhibitory effect, exogenous Tat protein stimulates HCMV replication. The interaction between HCMV and HIV in hematopoietic progenitor cells is complex and depends on several factors that can have opposite effects.
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Affiliation(s)
- T Lazzarotto
- Institute of Microbiology, University of Bologna, Italy
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42
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Re MC, Furlini G, Zauli G, La Placa M. Human immunodeficiency virus type 1 (HIV-1) and human hematopoietic progenitor cells. Arch Virol 1994; 137:1-23. [PMID: 7526824 DOI: 10.1007/bf01311169] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Besides a progressive depletion of CD4+ T-lymphocytes, other peripheral blood cytopenias, (granulocytopenia, anemia and thrombocytopenia) are frequently observed in HIV-1 seropositive individuals, especially in patients with overt AIDS. Various experimental evidences suggest that HIV-1 could play a direct role in the pathogenesis of HIV-1 related peripheral blood cytopenias, affecting the survival/proliferation capacity of hematopoietic progenitors. CD34+ human hematopoietic progenitors, however, are substantially not susceptible to HIV-1 infection either in vitro and in vivo and their defects seem rather related to an alteration of bone marrow and peripheral blood microenvironments due to the presence of soluble HIV-1 specific products.
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Affiliation(s)
- M C Re
- Institute of Microbiology, University of Bologna, St. Orsola General Hospital, Italy
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43
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Zauli G, Davis BR. Role of HIV infection in the hematologic manifestations of HIV seropositive subjects. Crit Rev Oncol Hematol 1993; 15:271-83. [PMID: 8142060 DOI: 10.1016/1040-8428(93)90045-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Affiliation(s)
- G Zauli
- Institute of Human Anatomy, University of Ferrara, Italy
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44
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Cen D, Zauli G, Szarnicki R, Davis BR. Effect of different human immunodeficiency virus type-1 (HIV-1) isolates on long-term bone marrow haemopoiesis. Br J Haematol 1993; 85:596-602. [PMID: 7510992 DOI: 10.1111/j.1365-2141.1993.tb03353.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Haemopoietic cytopenias are a frequent occurrence in human immunodeficiency virus type-1 (HIV-1) induced disease. In order to examine the possible direct inhibition of marrow haemopoiesis by HIV-1, we have investigated the effect of HIV-1 infection on myelopoiesis in long-term bone marrow cultures. In vitro exposure of normal marrow cultures to three different lymphocytotropic HIV-1 isolates resulted in productive infection, as demonstrated by a progressive increase of gag p24 antigen. In these experiments, ICR-3 isolate, but not LAV' or NL4-3 isolates, accelerated the loss of non-adherent cells. A differential ability of these HIV-1 isolates to suppress myelopoiesis was confirmed in long-term cultures in which virus was added continuously. In these cultures, ICR-3, and to a lesser extent also NL4-3, but not LAV', induced a progressive decrease in the number of total non-adherent cells as well as non-adherent colony forming units-granulocyte/macrophage (CFU-GM). Furthermore, exposure of normal purified CD34+ cells to ICR-3 induced defects in their ability to form haemopoietic colonies; this inhibitory effect was significantly relieved by pretreatment of ICR-3 with an anti-gp120 antibody. Similar exposure of CD34+ cells to LAV' and NL4-3 induced no such defects. These data indicate that some HIV-1 isolates can impair bone marrow haemopoiesis in a dose-dependent fashion, acting, at least in part, at the level of haemopoietic stem/progenitor cells.
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Affiliation(s)
- D Cen
- Geraldine Brush Cancer Research Institute, Medical Research Institute, San Francisco, CA 94115
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