One of the striking features of human immunodeficiency virus (HIV) is the capsid, a fullerene cone comprised of pleomorphic capsid protein (CA) that shields the viral genome and recruits cofactors. Despite significant advances in understanding the mechanisms of HIV-1 CA assembly and host factor interactions, HIV-2 CA assembly remains poorly understood. By templating the assembly of HIV-2 CA on functionalized liposomes, we report high-resolution structures of the HIV-2 CA lattice, including both CA hexamers and pentamers, alone and with peptides of host phenylalanine-glycine (FG)-motif proteins Nup153 and CPSF6. While the overall fold and mode of FG-peptide binding is conserved with HIV-1, this study reveals distinctive features of the HIV-2 CA lattice, including differing structural character at regions of host factor interactions and divergence in the mechanism of formation of CA hexamers and pentamers. This study extends our understanding of HIV capsids and highlights an approach facilitating the study of lentiviral capsid biology.

Coronavirus Disease 19 (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and Human Immunodeficiency Virus (HIV) are significant 21st-century pandemics with distinct virological and clinical characteristics. COVID-19 primarily presents as an acute respiratory illness, while HIV leads to chronic immune suppression. Understanding their differences can enhance public health strategies and treatment approaches.

This narrative review compares the virology, transmission, immune responses, and clinical outcomes of SARS-CoV-2 and HIV to inform treatment strategies and public health interventions.

A narrative review was conducted, synthesizing data from peer-reviewed literature and expert commentary from 2010 to 2024. Databases such as PubMed, Cochrane Library, and Google Scholar were searched for relevant studies.

SARS-CoV-2 primarily spreads through airborne droplets and contaminated surfaces, while HIV transmits through direct contact with infected bodily fluids. The immune response to SARS-CoV-2 involves both innate and adaptive systems, potentially leading to a cytokine storm in severe cases. In contrast, HIV evades the immune system by integrating into host cells, resulting in chronic infection and progressive immune deterioration. Treatment for SARS-CoV-2 focuses on symptom management and prevention, with antiviral medications and vaccines playing crucial roles. Conversely, HIV treatment relies on antiretroviral therapy (ART) to suppress viral replication and maintain immune function.

The review highlights the acute nature of SARS-CoV-2 versus the chronic progression of HIV. Tailored prevention and treatment strategies are essential for effective disease management.

Public health strategies should address the unique transmission routes and progression of both viruses. Further research into vaccine development and therapeutic interventions is critical for improving disease management.

Human immunodeficiency virus (HIV) targets the host immune system causing acquired immunodeficiency syndrome (AIDS). Although significant advancements have been made on investigating HIV and related infections, eradicating the virus from the host immune system is still challenging. Nevertheless, the combination therapies using drugs targeting different stages in the viral life cycle are used for treatment in which HIV protease plays a vital role. Hence, it is essential to understand the structure and function of HIV protease. This review focuses on these aspects from different perspectives such as catalytic mechanism, subtypes and role of flaps in drug binding. Further, we highlight the factors affecting drug binding, evolution of drug resistance, and inhibitors reported in the literature using 3D QSAR studies.

Cell-based therapies represent a major advancement in the treatment and management of HIV/AIDS, with a goal to overcome the limitations of traditional antiretroviral therapy (ART). These innovative approaches not only promise a functional cure by reconstructing the immune landscape but also address the persistent viral reservoirs. For example, stem cell therapies have emerged from the foundational success of allogeneic hematopoietic stem cell transplantation in curing HIV infection in a limited number of cases. B cell therapies make use of genetically modified B cells constitutively expressing broadly neutralizing antibodies (bNAbs) against target viral particles and infected cells. Adoptive cell transfer (ACT), including TCR-T therapy, CAR-T cells, NK-CAR cells, and DC-based therapy, is adapted from cancer immunotherapy and repurposed for HIV eradication. In this review, we summarize the mechanisms through which these engineered cells recognize and destroy HIV-infected cells, the modification strategies, and their role in sustaining remission in the absence of ART. The review also addresses the challenges to cell-based therapies against HIV and discusses the recent advancements aimed at overcoming them.

The Human Immunodeficiency Virus (HIV) is one of the greatest public health challenges still facing communities worldwide, and until this moment, no vaccine is available for its prevention. In Brazil, the Rio de Janeiro State has stood out regarding the prevalence of this disease. As a result, an important state to consider the Willingness to Pay (WTP) for a hypothetical HIV vaccine to help with future pricing.

A cross-sectional study was conducted to assess the acceptability and WTP of individuals from Rio de Janeiro State for a hypothetical HIV vaccine with a 70% efficacy.

600 individuals were interviewed and the acceptability for this hypothetical vaccine was 77.2%. In addition, 452 participants were eligible for the WTP analysis and would accept a WTP US$79.37 (400 BRL) for this vaccine, a higher value than that found in another study (200 BRL) conducted in the Northern region of Brazil under the same methodological conditions.

Economic studies such as WTP can contribute to discussions regarding the prices and specifications for future vaccines, particularly for a HIV vaccine in countries such as Brazil with over 5,000 municipalities spread across regions with diverse characteristics and challenges in terms of socioeconomic, epidemiological and cultural differences.

Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered to be undruggable targets have become increasingly feasible due to the progress that has been made over the last two decades and the rapid technological advances. This work explores the influence of technological innovations on PPI research and development. Additionally, the diverse strategies for discovering, modulating, and characterizing PPIs and their corresponding modulators are examined with the aim of presenting a streamlined pipeline for advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in PPI modulator discovery and development, we aim to illustrate the efficacy of various strategies for identifying, optimizing, and overcoming challenges associated with PPI modulator design. The valuable lessons and insights gained from the identification, optimization, and approval of PPI modulators are discussed with the aim of demonstrating that PPI modulators have transitioned beyond early-stage drug discovery and now represent a prime opportunity with significant potential. The selected examples of PPI modulators encompass those developed for cancer, inflammation and immunomodulation, as well as antiviral applications. This perspective aims to establish a foundation for the effective targeting and modulation of PPIs using PPI modulators and pave the way for future drug development.

Our world is ever evolving and interconnected, creating constant opportunities for disease outbreaks and pandemics to occur, making pandemic preparedness and pathogen management crucial for global health security. Early pathogen identification and intervention play a key role in mitigating the impacts of disease outbreaks. In this perspective, we present the Viral Trait Assessment for Pandemics (ViTAP) model to aid in the early identification of high-risk viruses that have pandemic potential, which incorporates lessons from past pandemics, including which key viral characteristics are important such as genetic makeup, transmission modes, mutation rates, and symptom severity. This model serves as the foundation for the development of powerful, quantitative tools for the early prediction of pandemic pathogens. The use of such a tool, in conjunction with other pandemic preparedness measures, can allow for early intervention and containment of the virus. This proactive approach could enable timely interventions, guiding public health responses, and resource allocation to prevent widespread outbreaks and mitigate the impact of emerging pathogens.

One of the most striking features of HIV is the capsid; a fullerene cone comprised of the pleomorphic capsid protein (CA) which shields the viral genome from cellular defense mechanisms and recruits cellular cofactors to the virus. Despite significant advances in understanding the mechanisms of HIV-1 CA assembly and host factor interaction, HIV-2 CA remains poorly understood. By templating the assembly of HIV-2 CA on functionalized liposomes, we were able to determine high resolution structures of the HIV-2 CA lattice, including both CA hexamers and pentamers, alone and in complexes with peptides of host phenylalanine-glycine (FG)-motif proteins Nup153 and CPSF6. While the overall fold and mode of binding the FG-peptides are conserved with HIV-1, this study reveals distinctive structural features that define the HIV-2 CA lattice, potential differences in interactions with other host factors such as CypA, and divergence in the mechanism of formation of hexameric and pentameric CA assemblies. This study extends our understanding of HIV capsids and highlights an approach with significant potential to facilitate the study of lentiviral capsid biology.

Synthetic helical peptidic foldamers show promising applications in chemical biology and biomedical sciences by mimicking protein helical segments. Sulfonyl-γ-AApeptide helices developed by our group exhibit good chemodiversity, predictable folding structures, proteolytic resistance, favorable cell permeability, and enhanced bioavailability. Herein, in this minireview, we highlight two recent examples of homogeneous left-handed sulfonyl-γ-AApeptide helices to modulate protein-protein interactions (PPIs). One is sulfonyl-γ-AApeptides as anti-HIV-1 fusion inhibitors mimicking the helical C-terminal heptad repeat (CHR), which show excellent anti-HIV-1 activities through tight binding with the N-terminal heptad repeat (NHR) and inhibiting the formation of the 6-helical bundle (HB) structure. Another example is helical sulfonyl-γ-AApeptides disrupting hypoxia-inducible factor 1α (HIF-1α) and p300 PPI, thus selectively inhibiting the relevant signaling cascade. We hope these findings could help to elucidate the principles of the structural design of sulfonyl-γ-AApeptides and inspire their future applications in PPI modulations.

Human immunodeficiency virus (HIV) is a significant global health issue that affects a substantial number of individuals across the globe, with a total of 39 million individuals living with HIV/AIDS. ART has resulted in a reduction in HIV-related mortality. Nevertheless, the issue of medication resistance is a significant obstacle in the management of HIV/AIDS. The unique genetic composition of HIV enables it to undergo rapid mutations and adapt, leading to the emergence of drug-resistant forms. The development of drug resistance can be attributed to various circumstances, including noncompliance with treatment regimens, insufficient dosage, interactions between drugs, viral mutations, preexposure prophylactics, and transmission from mother to child. It is therefore essential to comprehend the molecular components of HIV and the mechanisms of antiretroviral medications to devise efficacious treatment options for HIV/AIDS.

Currently, human immunodeficiency virus and acquired immunodeficiency syndrome (HIV/AIDS) has become one of the major health problems worldwide, including Indonesia. East Java is one of the provinces in Indonesia with the highest prevalence of HIV infection. One of the causes of HIV infection transmission is lesbian, gay, bisexual, and transgender (LGBT) practice. Furthermore, the treatment using antiretroviral (ARV) drugs in HIV-1 patients can fail due to the presence of HIV drug resistance.

The aim of this study is to identify the behavior at risk of HIV transmission among LGBT, patterns of genetic variation and antiretroviral (ARV) resistance.

A systematic review and meta-analysis based on the PRISMA guidelines was conducted. We searched three databases including PubMed, ScienceDirect, and Google scholar for studies investigating the non-heterosexual behavior as risk factor of HIV infection and antiretroviral resistance. Only studies published in English are considered. The adjusted estimates of the risk were carried out using best-adjusted OR with 95% confidence interval (CI) and significant p value < 0.05.

In the quantitative analysis of HIV infection risk factors, a total of 13 studies were included, which investigated non-heterosexual behavior as a potential factor. The studies involved a total of 37,129 participants, comprising 10,449 individuals in the non-heterosexual behavior group (LGBTQ+) and 26,680 individuals in the heterosexual group. The majority of the participants in this study were from the USA, Japan, China, and Brazil, and the main HIV subgenotypes were B and CRF. Additionally, the antiretroviral resistance of HIV patients was examined, involving a total of 3062 individuals, with 1296 individuals in the non-heterosexual behavior group and 1766 individuals in the heterosexual group. Our calculation showed that non-heterosexual behavior was significant as risk factor of HIV infection (OR = 2.17, 95% CI = 1.94-2.43, p < 0.001) and antiretroviral resistance (OR = 1.31, 95% CI = 1.00-1.71, p = 0.05).

This study concludes that non heterosexual behavior is significant risk factor of HIV infection. A quite prevalent of antiretroviral resistance were found among non heterosexual behavior. The main subgenotype of HIV are B and CRF.

Continually repeating outbreaks of pathogenic viruses necessitate the construction of effective antiviral strategies. Therefore, the development of new specific antiviral drugs in a well-established and efficient manner is crucial. Taking into account the strong ability of viruses to change, therapies with diversified molecular targets must be sought. In addition to the widely explored viral enzyme inhibitor approach, inhibition of protein-protein interactions is a very valuable strategy. In this Perspective, protein-protein interaction inhibitors targeting HIV, SARS-CoV-2, HCV, Ebola, Dengue, and Chikungunya viruses are reviewed and discussed. Antibodies, peptides/peptidomimetics, and small molecules constitute three classes of compounds that have been explored, and each of them has some advantages and disadvantages for drug development.

Acquired Immunodeficiency Syndrome is caused by the Human Immunodeficiency Virus (HIV), and a significant number of fatalities occur annually. There is a dire need to develop an effective vaccine against HIV-1. Understanding the structural proteins of viruses helps in designing a vaccine based on immunogenic peptides. In the current experiment, we identified gp120 epitopes using bioinformatic epitope prediction tools, molecular docking, and MD simulations. The Gb-1 peptide was considered an adjuvant. Consecutive sequences of GTG, GSG, GGTGG, and GGGGS linkers were used to bind the B cell, Cytotoxic T Lymphocytes (CTL), and Helper T Lymphocytes (HTL) epitopes. The final vaccine construct consisted of 315 amino acids and is expected to be a recombinant protein of approximately 35.49 kDa. Based on docking experiments, molecular dynamics simulations, and tertiary structure validation, the analysis of the modeled protein indicates that it possesses a stable structure and can interact with Toll-like receptors. The analysis demonstrates that the proposed vaccine can provoke an immunological response by activating T and B cells, as well as stimulating the release of IgA and IgG antibodies. This vaccine shows potential for HIV-1 prophylaxis. The in-silico design suggests that multiple-epitope constructs can be used as potentially effective immunogens for HIV-1 vaccine development.

The human immunodeficiency virus (HIV) epidemic is a global issue. The estimated number of people with HIV is 39,000,000 to date. Antiviral therapy is the primary approach to treat the infection. However, it does not allow for a complete elimination of the pathogen. The advances in modern gene therapy methods open up new possibilities of effective therapy. One of these areas of possibility is the development of technologies to prevent virus penetration into the cell. Currently, a number of technologies aimed at either the prevention of virus binding to the CCR5 coreceptor or its knockout are undergoing various stages of clinical trials. Since HIV can also utilize the CXCR4 coreceptor, technologies to modify this receptor are also required. Standard knockout of CXCR4 is impossible due to its physiological significance. This review presents an analysis of interactions between individual amino acids in CXCR4 and physiological ligands and HIV gp120. It also discusses potential targets for gene therapy approaches aimed at modifying the coreceptor.

The theory of immune regulation involves a homeostatic balance between T-helper 1 (Th1) and T-helper 2 (Th2) responses. The Th1 and Th2 theories were introduced in 1986 as a result of studies in mice, whereby T-helper cell subsets were found to direct different immune response pathways. Subsequently, this hypothesis was extended to human immunity, with Th1 cells mediating cellular immunity to fight intracellular pathogens, while Th2 cells mediated humoral immunity to fight extracellular pathogens. Several disease conditions were later found to tilt the balance between Th1 and Th2 immune response pathways, including HIV infection, but the exact mechanism for the shift from Th1 to Th2 cells was poorly understood. This review provides new insights into the molecular biology of HIV, wherein the HIV life cycle is discussed in detail. Insights into the possible mechanism for the Th1 to Th2 shift during HIV infection and the preferential infection of Th2 cells during the late symptomatic stage of HIV disease are also discussed.

Twenty-five years after the first report that HIV-2 infection can reduce HIV-1-associated pathogenesis in dual-infected patients, the mechanisms are still not well understood. We explored these mechanisms in cell culture and showed first that these viruses can co-infect individual cells. Under specific conditions, HIV-2 inhibits HIV-1 through two distinct mechanisms, a broad-spectrum interferon response and an HIV-1-specific inhibition conferred by the HIV-2 TAR. The former could play a prominent role in dually infected individuals, whereas the latter targets HIV-1 promoter activity through competition for HIV-1 Tat binding when the same target cell is dually infected. That mechanism suppresses HIV-1 transcription by stalling RNA polymerase II complexes at the promoter through a minimal inhibitory region within the HIV-2 TAR. This work delineates the sequence of appearance and the modus operandi of each mechanism.

Optimization of compound 11L led to the identification of novel HIV capsid modulators, quinazolin-4-one-bearing phenylalanine derivatives, displaying potent antiviral activities against both HIV-1 and HIV-2. Notably, derivatives 12a2 and 21a2 showed significant improvements, with 2.5-fold over 11L and 7.3-fold over PF74 for HIV-1, and approximately 40-fold over PF74 for HIV-2. The X-ray co-crystal structures confirmed the multiple pocket occupation of 12a2 and 21a2 in the binding site. Mechanistic studies revealed a dual-stage inhibition profile, where the compounds disrupted capsid-host factor interactions at the early stage and promoted capsid misassembly at the late stage. Remarkably, 12a2 and 21a2 significantly promoted capsid misassembly, outperforming 11L, PF74, and LEN. The substitution of easily metabolized amide bond with quinolin-4-one marginally enhanced the stability of 12a2 in human liver microsomes compared to controls. Overall, 12a2 and 21a2 highlight their potential as potent HIV capsid modulators, paving the way for future advancements in anti-HIV drug design.

Human immunodeficiency virus (HIV) is a major public health concern, particularly in Africa where HIV rates remain substantial. Pregnant women are at an increased risk of acquiring HIV, which has a significant impact on both maternal and child health.

To review summarizes HIV seroprevalence among pregnant women in Africa. It also identifies regional and clinical characteristics that contribute to study-specific estimates variation.

The study included pregnant women from any African country or region, irrespective of their symptoms, and any study design conducted in any setting. Using electronic literature searches, articles published until February 2023 were reviewed. The quality of the included studies was evaluated. The DerSimonian and Laird random-effects model was applied to determine HIV pooled seroprevalence among pregnant women in Africa. Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity. Heterogeneity was assessed with Cochran's Q test and I2 statistics, and publication bias was assessed with Egger's test.

A total of 248 studies conducted between 1984 and 2020 were included in the quantitative synthesis (meta-analysis). Out of the total studies, 146 (58.9%) had a low risk of bias and 102 (41.1%) had a moderate risk of bias. No HIV-positive pregnant women died in the included studies. The overall HIV seroprevalence in pregnant women was estimated to be 9.3% [95% confidence interval (CI): 8.3-10.3]. The subgroup analysis showed statistically significant heterogeneity across subgroups (P < 0.001), with the highest seroprevalence observed in Southern Africa (29.4%, 95%CI: 26.5-32.4) and the lowest seroprevalence observed in Northern Africa (0.7%, 95%CI: 0.3-1.3).

The review found that HIV seroprevalence among pregnant women in African countries remains significant, particularly in Southern African countries. This review can inform the development of targeted public health interventions to address high HIV seroprevalence in pregnant women in African countries.

Virus infection has been one of the main causes of human death since the ancient times. Even though more and more antiviral drugs have been approved in clinic, long-term use can easily lead to the emergence of drug resistance and side effects. Fortunately, there are many kinds of metabolites which were produced by plants, marine organisms and microorganisms in nature with rich structural skeletons, and they are natural treasure house for people to find antiviral active substances. Aiming at many types of viruses that had caused serious harm to human health in recent years, this review summarizes the natural products with antiviral activity that had been reported for the first time in the past ten years, we also sort out the source, chemical structure and safety indicators in order to provide potential lead compounds for the research and development of new antiviral drugs.

Although some individuals with HIV-2 develop severe immunodeficiency and AIDS-related complications, most may never progress to AIDS. Replication-competent HIV-2 isolated from asymptomatic long-term non-progressors (controllers) have lower replication rates than viruses from individuals who progress to AIDS (progressors). To investigate potential retroviral factors that correlate with disease progression in HIV-2, we sequenced the near full-length genomes of replication-competent viruses previously outgrown from controllers and progressors and used phylogeny to seek genotypic correlates of disease progression. We validated the integrity of all open reading frames and used cell-based assays to study the retroviral transcriptional activity of the long terminal repeats (LTRs) and Tat proteins of HIV-2 from controllers and progressors. Overall, we did not identify genotypic defects that may contribute to HIV-2 non-progression. Tat-induced, LTR-mediated transcription was comparable between viruses from controllers and progressors. Our results were obtained from a small number of participants and should be interpreted accordingly. Overall, they suggest that progression may be determined before or during integration of HIV-2.

Chalcones and their derivatives have been widely studied due to their versatile pharmacological and biological activities, such as anti-inflammatory, antibacterial, antiviral, and antitumor effects. These compounds have shown suitable antiviral effects through the selective targeting of a variety of viral enzymes, including lactate dehydrogenase, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), fumarate reductase, protein tyrosine phosphatase, topoisomerase-II, protein kinases, integrase/protease, and lactate/isocitrate dehydrogenase, among others. Chalcones and their derivatives have displayed excellent potential for combating pathogenic bacteria and fungi (especially, multidrug-resistant bacteria). However, relevant mechanisms should be further explored, focusing on inhibitory effects against DNA gyrase B, UDP-N-acetylglucosamine enolpyruvyl transferase (MurA), and efflux pumps (e.g., NorA), among others. In addition, the antifungal and antiparasitic activities of these compounds (e.g., antitrypanosomal and antileishmanial properties) have prompted additional explorations. Nonetheless, systematic analysis of the relevant mechanisms, biosafety issues, and pharmacological properties, as well as clinical translation studies, are vital for practical applications. Herein, recent advancements pertaining to the antibacterial, antiviral, antiparasitic, and antifungal activities of chalcones and their derivatives are deliberated, focusing on the relevant mechanisms of action, crucial challenges, and future prospects. Furthermore, due to the great importance of greener and more sustainable synthesis of these valuable compounds, especially on an industrial scale, the progress made in this field has been briefly discussed. Hopefully, this review can serve as a catalyst for researchers to delve deeper into the exploration and designing of novel chalcone compounds with medicinal properties, especially against pathogenic viruses and multidrug-resistant bacteria as major causes of concern for human health.

A better understanding of HIV-1 latency is a research priority in HIV cure research. Conversely, little is known about the latency characteristics of HIV-2, the closely related human lentivirus. Though both viruses cause AIDS, HIV-2 infection progresses more slowly with significantly lower viral loads, even when corrected for CD4+ T cell counts. Hence a direct comparison of latency characteristics between HIV-1 and HIV-2 could provide important clues towards a functional cure. Transduction of SupT1 cells with single-round HIV-1 and HIV-2 viruses with an enhanced green fluorescent protein (eGFP) reporter showed higher levels of eGFP expression for HIV-2 than HIV-1, while HIV-1 expression appeared more cytotoxic. To compare HIV-1 and HIV-2 gene expression, latency and reactivation in more detail, we have generated HIV-2 OGH, a replication deficient, near full- length, double reporter virus that discriminates latently and productively infected cells in cell culture. This construct is based on HIV-1 OGH, and to our knowledge, first of its kind for HIV-2. Using this construct we have observed a higher eGFP expression for HIV-2, but higher losses of HIV-1 transduced cells in SupT1 and Jurkat cells and a reduced sensitivity of HIV-2 for reactivation with TNF-α. In addition, we have analysed HIV-2 integration sites and their epigenetic environment. HIV-1 and HIV-2 share a preference for actively transcribed genes in gene-dense regions and favor active chromatin marks while disfavoring methylation markers associated with heterochromatin. In conclusion the HIV-2 OGH construct provides an interesting tool for studying HIV-2 expression, latency and reactivation. As simian immunodeficiency virus (SIV) and HIV-2 have been proposed to model a functional HIV cure, a better understanding of the mechanisms governing HIV-2 and SIV latency will be important to move forward. Further research is needed to investigate if HIV-2 uses similar mechanisms as HIV-1 to achieve its integration site selectivity.

The human immunodeficiency virus type 1 (HIV-1) reservoir, composed of cells harboring the latent, integrated virus, is not eliminated by antiretroviral therapy. It therefore represents a significant barrier to curing the infection. The biology of HIV-1 reservoirs, the mechanisms of their persistence, and effective strategies for their eradication are not entirely understood. Here, we review the molecular mechanisms by which HIV-1 reservoirs develop, the cells and compartments where the latent virus resides, and advancements in curative therapeutic strategies. We first introduce statistics and relevant data on HIV-1 infection, aspects of pathogenesis, the role of antiretroviral therapy, and the general features of the latent HIV reservoir. Then, the article is built on three main pillars: The molecular mechanisms related to latency, the different strategies for targeting the reservoir to obtain a cure, and the current progress in immunotherapy to counteract said reservoirs.

Retrovirus immature particle morphology consists of a membrane enclosed, pleomorphic, spherical and incomplete lattice of Gag hexamers. Previously, we demonstrated that human immunodeficiency virus type 2 (HIV-2) immature particles possess a distinct and extensive Gag lattice morphology. To better understand the nature of the continuously curved hexagonal Gag lattice, we have used the single particle cryo-electron microscopy method to determine the HIV-2 Gag lattice structure for immature virions. The reconstruction map at 5.5 Å resolution revealed a stable, wineglass-shaped Gag hexamer structure with structural features consistent with other lentiviral immature Gag lattice structures. Cryo-electron tomography provided evidence for nearly complete ordered Gag lattice structures in HIV-2 immature particles. We also solved a 1.98 Å resolution crystal structure of the carboxyl-terminal domain (CTD) of the HIV-2 capsid (CA) protein that identified a structured helix 12 supported via an interaction of helix 10 in the absence of the SP1 region of Gag. Residues at the helix 10-12 interface proved critical in maintaining HIV-2 particle release and infectivity. Taken together, our findings provide the first 3D organization of HIV-2 immature Gag lattice and important insights into both HIV Gag lattice stabilization and virus maturation.

Ribonucleic acid (RNA) is of great interest in many different therapeutic areas including infectious diseases such as immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Thanks to current, advanced treatments for HIV, the diagnosis is no longer a death sentence. However, even with these treatments, latency is suggested to persist in T-lymphocyte-rich tissues including gut-associated lymphatic tissue (GALT), spleen, and bone marrow making HIV an incurable disease. Therefore, it is important to design systems that can effectively deliver therapeutics to these tissues to fight latent infection and find a functional cure. Numerous therapeutics ranging from small molecules to cell therapies have been explored as a cure for HIV but have failed to maintain therapeutic longevity. RNA interference (RNAi) provides a unique opportunity to achieve a functional cure for those who suffer from chronic HIV/AIDS by suppressing replication of the virus. However, RNA has certain imitations in delivery as it cannot be delivered without a carrier due to its negative charge and degradation from endogenous nucleases. Here, we provide a detailed analysis of explored systems for siRNA delivery for HIV/AIDS in the context of RNA therapeutic design and nanoparticle design. In addition, we suggest strategies that should be used to target specific tissues that are rich in lymphatic tissue.

The perfect storm model that was elaborated for the HIV-1M pandemic has also been used to explain the emergence of HIV-2, a second human immunodeficiency virus-acquired immunodeficiency syndrome (HIV-AIDS) that became an epidemic in Guinea-Bissau, West Africa. The use of this model creates epidemiological generalizations, ecological oversimplifications and historical misunderstandings as its assumptions-an urban center with explosive population growth, a high level of commercial sex and a surge in STDs, a network of mechanical transport and country-wide, en masse mobile campaigns-are absent from the historical record. This model fails to explain how the HIV-2 epidemic actually came about. This is the first study to conduct an exhaustive examination of sociohistorical contextual developments and align them with environmental, virological and epidemiological data. The interdisciplinary dialogue indicates that the emergence of the HIV-2 epidemic piggybacked on local sociopolitical transformations. The war's indirect effects on ecological relations, mobility and sociability were acute in rural areas and are a key to the HIV-2 epidemic. This setting had the natural host of the virus, the population numbers, the mobility trends and the use of technology on a scale needed to foster viral adaptation and amplification. The present analysis suggests new reflections on the processes of zoonotic spillovers and disease emergence.

Persistent infection with high-risk human papillomavirus (HPV) is associated with development of invasive cervical cancer.

Longitudinal data was collected from 174 Senegalese women. We employed marginal Cox proportional hazards models to examine the effect of human immunodeficiency virus (HIV) status (HIV positive vs HIV negative) and HIV type (HIV-1 vs HIV-2 vs dual HIV-1/HIV-2) on clearance of type-specific HPV infection. Analyses were stratified by incident versus prevalent HPV infection.

Incident HPV infections in HIV-positive women were less likely to clear than those in HIV-negative women (adjusted hazard ratio [HR] = 0.60; 95% confidence interval [CI], .38-.94). Among HIV-positive women, HIV-2-infected women and HIV-1/2 dually infected women were more likely to clear HPV incident infections than HIV-1-infected women (HR = 1.66; 95% CI, .95-2.92 and HR = 2.17; 95% CI, 1.12-4.22, respectively). Incident HPV infections in HIV-positive women with CD4 cell count ≤500 cells/μL were less likely to clear than those in HIV-positive women with CD4 cell count >500 cells/μL (HR = 0.65; 95% CI, .42-1.01). No significant associations were observed for prevalent HPV infections.

HIV infection reduced the likelihood of clearance of incident HPV infection. Furthermore, among HIV-positive women, low CD4 cell count and dual HIV infection were each associated with reduced likelihood of clearance.

Macrophages (Mø) and dendritic cells (DCs) are key players in human immunodeficiency virus (HIV) infection and pathogenesis. They are essential for the spread of HIV to CD4+ T lymphocytes (TCD4+) during acute infection. In addition, they constitute a persistently infected reservoir in which viral production is maintained for long periods of time during chronic infection. Defining how HIV interacts with these cells remains a critical area of research to elucidate the pathogenic mechanisms of acute spread and sustained chronic infection and transmission. To address this issue, we analyzed a panel of phenotypically distinct HIV-1 and HIV-2 primary isolates for the efficiency with which they are transferred from infected DCs or Mø to TCD4+. Our results show that infected Mø and DCs spread the virus to TCD4+ via cell-free viral particles in addition to other alternative pathways. We demonstrate that the production of infectious viral particles is induced by the co-culture of different cell populations, indicating that the contribution of cell signaling driven by cell-to-cell contact is a trigger for viral replication. The results obtained do not correlate with the phenotypic characteristics of the HIV isolates, namely their co-receptor usage, nor do we find significant differences between HIV-1 and HIV-2 in terms of cis- or trans-infection. The data presented here may help to further elucidate the cell-to-cell spread of HIV and its importance in HIV pathogenesis. Ultimately, this knowledge is critical for new therapeutic and vaccine approaches.

CD8⁺ T cells equipped with a full arsenal of antiviral effector functions are critical for effective immune control of HIV-1. It has nonetheless remained unclear how best to elicit such potent cellular immune responses in the context of immunotherapy or vaccination. HIV-2 has been associated with milder disease manifestations and more commonly elicits functionally replete virus-specific CD8⁺ T cell responses compared with HIV-1. We aimed to learn from this immunological dichotomy and to develop informed strategies that could enhance the induction of robust CD8⁺ T cell responses against HIV-1.

We developed an unbiased in vitro system to compare the de novo induction of antigen-specific CD8⁺ T cell responses after exposure to HIV-1 or HIV-2. The functional properties of primed CD8⁺ T cells were assessed using flow cytometry and molecular analyses of gene transcription.

HIV-2 primed functionally optimal antigen-specific CD8⁺ T cells with enhanced survival properties more effectively than HIV-1. This superior induction process was dependent on type I interferons (IFNs) and could be mimicked via the adjuvant delivery of cyclic GMP-AMP (cGAMP), a known agonist of the stimulator of interferon genes (STING). CD8⁺ T cells elicited in the presence of cGAMP were polyfunctional and highly sensitive to antigen stimulation, even after priming from people living with HIV-1.

HIV-2 primes CD8⁺ T cells with potent antiviral functionality by activating the cyclic GMP-AMP synthase (cGAS)/STING pathway, which results in the production of type I IFNs. This process may be amenable to therapeutic development via the use of cGAMP or other STING agonists to bolster CD8⁺ T cell-mediated immunity against HIV-1.

This work was funded by INSERM, the Institut Curie, and the University of Bordeaux (Senior IdEx Chair) and by grants from Sidaction (17-1-AAE-11097, 17-1-FJC-11199, VIH2016126002, 20-2-AEQ-12822-2, and 22-2-AEQ-13411), the Agence Nationale de la Recherche sur le SIDA (ECTZ36691, ECTZ25472, ECTZ71745, and ECTZ118797), and the Fondation pour la Recherche Médicale (EQ U202103012774). D.A.P. was supported by a Wellcome Trust Senior Investigator Award (100326/Z/12/Z).

HIV-1 remains a global health concern and to date, nearly 38 million people are living with HIV. The complexity of HIV-1 pathogenesis and its subsequent prevalence is influenced by several factors including the HIV-1 subtype. HIV-1 subtype variation extends to sequence variation in the amino acids of the HIV-1 viral proteins. Of particular interest is the transactivation of transcription (Tat) protein due to its key function in viral transcription. The Tat protein predominantly functions by binding to the transactivation response (TAR) RNA element to activate HIV-1 transcriptional elongation. Subtype-specific Tat protein sequence variation influences Tat-TAR binding affinity. Despite several studies investigating Tat-TAR binding, it is not clear which regions of the Tat protein and/or individual Tat amino acid residues may contribute to TAR binding affinity. We, therefore, conducted a scoping review on studies investigating Tat-TAR binding. We aimed to synthesize the published data to determine (1) the regions of the Tat protein that may be involved in TAR binding, (2) key Tat amino acids involved in TAR binding and (3) if Tat subtype-specific variation influences TAR binding. A total of thirteen studies met our inclusion criteria and the key findings were that (1) both N-terminal and C-terminal amino acids outside the basic domain (47-59) may be important in increasing Tat-TAR binding affinity, (2) substitution of the amino acids Lysine and Arginine (47-59) resulted in a reduction in binding affinity to TAR, and (3) none of the included studies have investigated Tat subtype-specific substitutions and therefore no commentary could be made regarding which subtype may have a higher Tat-TAR binding affinity. Future studies investigating Tat-TAR binding should therefore use full-length Tat proteins and compare subtype-specific variations. Studies of such a nature may help explain why we see differential pathogenesis and prevalence when comparing HIV-1 subtypes.

The Human Immunodeficiency Virus (HIV-1) causes Acquired Immunodeficiency Syndrome (AIDS) and a high percentage of deaths. Therefore, it is necessary to design vaccines against HIV-1 for the prevention of AIDS. Bioinformatic tools and theoretical algorisms allow us to understand the structural proteins of viruses to develop vaccines based on immunogenic peptides (epitopes). In this work, we identified the epitopes: P1, P2, P10, P27 and P30 from the gp120 protein of HIV-1. These peptides were administered intranasally alone or with cholera toxin (CT) to BALB/c mice. The population of CD4+, CD8+ T lymphocytes and B cells (CD19/CD138+, IgA+ and IgG+) from nasal-associated lymphoid tissue, nasal passages, cervical and inguinal nodes was determined by flow cytometry. In addition, anti-peptides IgG and IgA from serum, nasal and vaginal washings were measured by ELISA. The results show that peptides administered by i.n. can modulate the immune response of T and B lymphocyte populations, as well as IgA and IgG antibodies secretion in the different sites analyzed. In conclusion, bioinformatics tools help us to select peptides with physicochemical properties that allow the induction of the humoral and cellular responses that depend on the peptide sequence.

In resource limited settings, a cost-effective point-of-care diagnostic testing possessing the characteristics of detecting the minimum viral load of a malady like human immunodeficiency virus (HIV) acquired immune deficiency syndrome (AIDS) is a pressing priority. The present work describes a novel, rapid and field-deployable method using surface enhanced Raman spectroscopy (SERS) for detection and prognosis of HIV positive clinical samples, in seven different viral load ranges varying between 200 and 1 million copies/ml. A relationship between the increasing and decreasing intensity peaks of HIV-1 was also established for quantitation efficacy of the handheld tool. Three different types of SERS substrates: single arm Ag nanorods, double arm Ag nanorods and Au sputtered single arm Ag nanorods were used and the obtained data was compared for the three substrates. It was demonstrated that maximum enhancement was obtained for Au sputtered Ag nanorods. Rigorous coupled wave analysis (RCWA) simulations were performed to study the 'hotspots' in three different SERS substrates. Further, to explore the utility of our platform and to differentiate between the clade specific X4 and R5 tropism, their corresponding SERS spectra were studied using HIV-1 strains belonging to four different HIV-1 subtypes (A, B, C and D) which showed a clear distinction, implying the usefulness of the platform in understanding the disease prognosis. Statistical analysis of the obtained SERS spectra using principal component analysis (PCA) showed good agreement with the experimental results, confirming the ability of SERS platform to quantitate HIV-1 viral load and distinguish HIV-1 strains on the basis of their SERS spectra.

To complete their replication cycle, retroviruses need to integrate a DNA copy of their RNA genome into a host chromosome. Integration site selection is not random and is driven by multiple viral and cellular host factors specific to different classes of retroviruses. Today, overwhelming evidence from cell culture, animal experiments and clinical data suggests that integration sites are important for retroviral replication, oncogenesis and/or latency. In this review, we will summarize the increasing knowledge of the mechanisms underlying the integration site selection of the gammaretrovirus MLV and the lentivirus HIV-1. We will discuss how host factors of the integration site selection of retroviruses may steer the development of safer viral vectors for gene therapy. Next, we will discuss how altering the integration site preference of HIV-1 using small molecules could lead to a cure for HIV-1 infection.

Introduction: HIV2 is endemic in West Africa. In Burkina Faso, its prevalence was estimated at 2%. The aim of this work was to evaluate the follow-up of patients and also to contribute to the availability of data. Methods: We involved 18 years or older. Infection was screened according to the national algorithm. A cross- sectional study from first June 2017 to 31 December 2017 was performed. For each patient, sociodemographic, clinical, biological, therapeutic and evolution data were collected and analyzed. Results: The proportion of patients infected with HIV2 (n  =  48; 1.7%) and HIV2  +  1 (n  =  67; 2.4%) was 4.3%. The sex rat mean age was 50.3  ±  8.5 years. The combination of 2INTI  +  LPV/r was the most prescribed (n  =  73; 63.5%). The average gain of LTCD4 has evolved from + 236 cells/mm³ in 2011 to + 364 cells/mm³ in 2015. The retention rate at grade 5 was about 70%. Conclusion: The immunological and clinic response of the patients was satisfactory. More than half of the patients remained in the continuum of care after five years of follow-up.

The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound FTC-2 is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound TD-1a has the lowest EC50 in the anti-HIV-2 assays (EC50 = 4.86 ± 1.71 μM; CC50= 86.54 ± 29.24 μM). A water solubility test found that TD-1a showed a moderately increased water solubility compared with PF74, while the water solubility of FTC-2 was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for FTC-2 and TD-1a. Based on this analysis, TD-1a is predicted to have improved drug-like properties and metabolic stability over PF74. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2.

Limited data are available on the pathogenesis of HIV-2, and the evolution of Env molecular properties during disease progression is not fully elucidated. We investigated the intra-patient evolution of molecular properties of HIV-2 Env regions (V1-C3) during the asymptomatic, treatment-naïve phase of the infection in 16 study participants, stratified into faster or slower progressors. Most notably, the rate of change in the number of potential N-linked glycosylation sites (PNGS) within the Env (V1-C3) regions differed between progressor groups. With declining CD4⁺ T-cell levels, slower progressors showed, on average, a decrease in the number of PNGSs, while faster progressors showed no significant change. Furthermore, diversity increased significantly with time in faster progressors, whereas no such change was observed in slower progressors. No differences were identified between the progressor groups in the evolution of length or charge of the analyzed Env regions. Predicted virus CXCR4 use was rare and did not emerge as a dominating viral population during the studied disease course (median 7.9 years, interquartile range [IQR]: 5.2-14.0) in either progressor groups. Further work building on our observations may explain molecular hallmarks of HIV-2 disease progression and differences in pathogenesis between HIV-1 and HIV-2.

Subtype B HIV-1 reservoirs have been intensively investigated, but reservoirs in other subtypes and how they respond to antiretroviral therapy (ART) is substantially less established. To characterize subtype C HIV-1 reservoirs, we implemented postmortem frozen, as well as formalin fixed paraffin embedded (FFPE) tissue sampling of central nervous system (CNS) and peripheral tissues. HIV-1 LTR, gag, envelope (env) DNA and RNA was quantified using genomic DNA and RNA extracted from frozen tissues. RNAscope was used to localize subtype C HIV-1 DNA and RNA in FFPE tissue. Despite uniform viral load suppression in our cohort, PCR results showed that subtype C HIV-1 proviral copies vary both in magnitude and tissue distribution, with detection primarily in secondary lymphoid tissues. Interestingly, the appendix harbored proviruses in all subjects. Unlike subtype B, subtype C provirus was rarely detectable in the CNS, and there was no detectable HIV-1 RNA. HIV-1 RNA was detected in peripheral lymphoid tissues of 6 out of 8 ART-suppressed cases. In addition to active HIV-1 expression in lymphoid tissues, RNAscope revealed HIV RNA detection in CD4-expressing cells in the appendix, suggesting that this tissue was a previously unreported potential treatment-resistant reservoir for subtype C HIV-1.

Human immunodeficiency virus (HIV) Gag drives virus particle assembly. The capsid (CA) domain is critical for Gag multimerization mediated by protein-protein interactions. The Gag protein interaction network defines critical aspects of the retroviral lifecycle at steps such as particle assembly and maturation. Previous studies have demonstrated that the immature particle morphology of HIV-2 is intriguingly distinct relative to that of HIV-1. Based upon this observation, we sought to determine the amino acid residues important for virus assembly that might help explain the differences between HIV-1 and HIV-2. To do this, we conducted site-directed mutagenesis of targeted locations in the HIV-2 CA domain of Gag and analyzed various aspects of virus particle assembly. A panel of 31 site-directed mutants of residues that reside at the HIV-2 CA inter-hexamer interface, intra-hexamer interface and CA inter-domain linker were created and analyzed for their effects on the efficiency of particle production, particle morphology, particle infectivity, Gag subcellular distribution and in vitro protein assembly. Seven conserved residues between HIV-1 and HIV-2 (L19, A41, I152, K153, K157, N194, D196) and two non-conserved residues (G38, N127) were found to significantly impact Gag multimerization and particle assembly. Taken together, these observations complement structural analyses of immature HIV-2 particle morphology and Gag lattice organization as well as provide important comparative insights into the key amino acid residues that can help explain the observed differences between HIV immature particle morphology and its association with virus replication and particle infectivity.

The human immunodeficiency virus (HIV) is currently one of the most pressing global health problems. Since its discovery in 1978, HIV has claimed the lives of more than 35 million people, and the number of people infected today reaches 37 million. In the absence of highly active antiretroviral therapy (HAART), HIV infection is characterized by a steady decrease in the number of CD4+ T-lymphocytes, but its manifestations can affect the central nervous, cardiovascular, digestive, endocrine and genitourinary systems. At the same time, complications induced by representatives of pathogenic and opportunistic microflora, which can lead to the development of bacterial, fungal and viral concomitant infections, are of particular danger. It should be borne in mind that an important problem is the emergence of viruses resistant to standard therapy, as well as the toxicity of the drugs themselves for the body. In the context of this review, of particular interest is the assessment of the prospects for the creation and clinical use of drugs based on small interfering RNAs aimed at suppressing the reproduction of HIV, taking into account the experience of similar studies conducted earlier. RNA interference is a cascade of regulatory reactions in eukaryotic cells, which results in the degradation of foreign messenger RNA. The development of drugs based on the mechanism of RNA interference will overcome the problem of viral resistance. Along with this, this technology makes it possible to quickly respond to outbreaks of new viral diseases.

Human immunodeficiency virus (HIV) is associated with altered cellular and humoral immune response, especially in patients with an untreated or chronic infection. This may be due to direct and/or indirect HIV viral activities resulting in T- and B-cells dysfunctions. Although still unclear, various studies have proposed that HIV infection may exacerbate the clinical outcomes of COVID-19. Indeed, COVID-19 vaccines were developed in record time and have been shown to reduce the severity of COVID-19 in the general population. These vaccines were also earmarked as a solution to global disruptions caused by the COVID-19 pandemic. HIV infection has been reported to reduce the efficacy of various other vaccines including those used against Streptococcus pneumoniae, Clostridium tetani, and influenza viruses. However, current guidelines for the administration of available COVID-19 vaccines do not account for the immune-compromised state of people living with HIV (PLWH). We discuss here the potentials, nature, and implications of this HIV-induced dampening of the humoral immune response on COVID-19 vaccines by first reviewing the literature about efficacy of previous vaccines in PLWH, and then assessing the proportion of PLWH included in phase III clinical trials of the COVID-19 vaccines currently available. The clinical and public health implications as well as suggestions for governments and non-governmental organizations are also proposed in the context of whether findings on the safety and efficacy of the vaccines could be extended to PLWH.

The human immunodeficiency virus (HIV) is characterized by attenuated humoral immunity that may reduce the efficacy of vaccines in people living with HIV (PLWH). Vaccination against the SARS-CoV-2 infection remains the main public health answer to the COVID-19 pandemic.Although no significant safety concerns have been raised regarding the COVID-19 vaccines in PLWH, the efficacy of these vaccines in PLWH has not received due attention. Indeed, phase III clinical trials for the safety and efficacy of COVID-19 vaccines involved a significantly low number of PLWH.There are major gaps in knowledge on the efficacy of COVID-19 vaccines in PLWH and until further research is carried out, PLWH should be prioritized along with other at-risk groups for repeated vaccination and safeguard.

HIV-1 must package its RNA genome to generate infectious viruses. Recent studies have revealed that during genome packaging, HIV-1 not only excludes cellular mRNAs, but also distinguishes among full-length viral RNAs. Using NL4-3 and MAL molecular clones, multiple transcription start sites (TSS) were identified, which generate full-length RNAs that differ by only a few nucleotides at the 5' end. However, HIV-1 selectively packages RNAs containing one guanosine (1G RNA) over RNAs with three guanosines (3G RNA) at the 5' end. Thus, the 5' context of HIV-1 full-length RNA can affect its function. To determine whether the regulation of genome packaging by TSS usage is unique to NL4-3 and MAL, we examined 15 primate lentiviruses including transmitted founder viruses of HIV-1, HIV-2, and several simian immunodeficiency viruses (SIVs). We found that all 15 viruses used multiple TSS to some extent. However, the level of TSS heterogeneity in infected cells varied greatly, even among closely related viruses belonging to the same subtype. Most viruses also exhibited selective packaging of specific full-length viral RNA species into particles. These findings demonstrate that TSS heterogeneity and selective packaging of certain full-length viral RNA species are conserved features of primate lentiviruses. In addition, an SIV strain closely related to the progenitor virus that gave rise to HIV-1 group M, the pandemic pathogen, exhibited TSS usage similar to some HIV-1 strains and preferentially packaged 1G RNA. These findings indicate that multiple TSS usage and selective packaging of a particular unspliced RNA species predate the emergence of HIV-1. IMPORTANCE Unspliced HIV-1 RNA serves two important roles during viral replication: as the virion genome and as the template for translation of Gag/Gag-Pol. Previous studies of two HIV-1 molecular clones have concluded that the TSS usage affects unspliced HIV-1 RNA structures and functions. To investigate the evolutionary origin of this replication strategy, we determined TSS of HIV-1 RNA in infected cells and virions for 15 primate lentiviruses. All HIV-1 isolates examined, including several transmitted founder viruses, utilized multiple TSS and selected a particular RNA species for packaging. Furthermore, these features were observed in SIVs related to the progenitors of HIV-1, suggesting that these characteristics originated from the ancestral viruses. HIV-2, SIVs related to HIV-2, and other SIVs also exhibited multiple TSS and preferential packaging of specific unspliced RNA species, demonstrating that this replication strategy is broadly conserved across primate lentiviruses.