Persistent HIV reservoirs in CD4+ T cells pose a barrier to curing HIV infection. We identify overexpression of enhancer of zeste homolog 2 (EZH2) in HIV-infected CD4+ T cells that survive cytotoxic T lymphocyte (CTL) exposure, suggesting a mechanism of CTL resistance. Inhibition of EZH2 with the US Food and Drug Administration-approved drug tazemetostat increases surface expression of major histocompatibility complex (MHC) class I on CD4+ T cells, counterbalancing HIV Nef-mediated MHC class I downregulation. This improves CTL-mediated elimination of HIV-infected cells and suppresses viral replication in vitro. In a participant-derived xenograft mouse model, tazemetostat elevates MHC class I and the pro-apoptotic protein BIM in CD4+ T cells, facilitating CD8+ T cell-mediated reductions of HIV reservoir seeding. Additionally, tazemetostat promotes sustained skewing of CD8+ T cells toward less-differentiated and exhausted phenotypes. Our findings reveal EZH2 overexpression as a mechanism of CTL resistance and support the clinical evaluation of tazemetostat as a method of enhancing clearance of HIV reservoirs and improving CD8+ T cell function.

Nonhuman primate (NHP) models of HIV-1 infection provide complementary experimental pathways for assessing aspects of acute HIV-1 infection (AHI) that cannot be addressed in humans. This article reviews acute infection studies in SIV-infected or SHIV-infected macaque species over the previous 18 months.

Reviewed studies examined the dynamics of replication-competent viral reservoir establishment during early infection, reservoir maintenance throughout therapy, and factors influencing viral rebound after treatment cessation. Also discussed are acute infection events in the central nervous system and liver and potential links between these events and manifestations of comorbidities during chronic infection. Additional studies addressed how occurrences during acute infection impact the development of natural viral control or posttreatment control. Another report evaluated treatment during acute infection with broadly neutralizing antibodies with enhanced ability to engage innate immune cells, highlighting the ability of this early intervention to shape innate and adaptive antiviral responses.

NHP models of HIV-1 infection are a fundamental research tool for investigating AHI events. These models enable detailed pathogenesis characterization and the testing of hypothesis-driven strategies for altering disease courses through interventions during AHI, including targeting viral persistence and comorbidities that persist throughout chronic infection.

There is currently no curative treatment for HIV-1 infection. However, some individuals (defined as posttreatment controllers) durably control viremia after the discontinuation of antiretroviral therapy (ART). Although the ability to achieve this HIV-1 remission status is enhanced by early treatment initiation, the mechanisms leading to posttreatment HIV-1 control remain unclear.

We retrospectively explored the immunogenetic characteristics of long-term posttreatment controllers from the ANRS VISCONTI study and persons monitored since primary HIV-1 infection in the ANRS PRIMO cohort and evaluated their influence on clinical parameters and outcome after ART discontinuation.

We identified a major histocompatibility complex (MHC)-related fingerprint favoring sustained HIV-1 remission. HLA-B∗35 alleles, which are associated with rapid progression to AIDS during natural HIV-1 infection, were paradoxically overrepresented among posttreatment controllers and had a positive impact on outcome after treatment discontinuation in people who began therapy during primary infection. Specifically, the influence of HLA-B∗35 alleles was observed when they were carried in combination with other HLA class I alleles expressing Bw4 and C2 ligands of killer immunoglobulin-like receptors (KIRs) in a genetic context that favors KIR education of natural killer (NK) cells (Bw4TTC2 genotype). Accordingly, posttreatment controllers with HLA-B∗35 alleles carry distinct KIR genotypes and NK cells.

The combination of HLA-B∗35 with Bw4TTC2 genotype, associated with KIR education of NK cells, was abundant among posttreatment HIV-1 controllers and promoted viral control after interruption of early-initiated antiretroviral treatment. These results support a role of NK cells in sustained HIV-1 remission.

The VISCONTI study and the PRIMO cohort are funded by the ANRS-MIE.

People living with HIV treated during acute infection are the group for whom achieving functional cure appears most viable. Follicular CD8+ T cells could contribute to HIV reservoir clearance by accessing B cell follicles through CXCR5 expression. This study examines peripheral follicular CD8+ T cells using flow cytometry, transcriptome analyses, and functional assays in people treated during acute (n = 37) and chronic (n = 18) infection, as well as in individuals naturally controlling HIV (n = 20) and living without HIV (n = 10). Our results reveal that early, as opposed to late, treatment initiation preserves antiviral effector functions of follicular CD8+ T cells, which are further enhanced by PD1 inhibition. We also identify a correlation between follicular CD8+ T cells and intact proviral HIV DNA levels in acute, but not chronic, infection. Longitudinal transcriptomic analysis of peripheral effector cells after 48 weeks of suppressive therapy indicated traits of recent antigen exposure, suggesting potential recirculation into lymphoid tissue. These findings underscore the pivotal role of follicular CD8+ T cells in anti-HIV responses and support investigating targeted cure strategies, such as anti-PD1 therapy, especially in individuals initiating treatment during acute infection.

Cross-reactive T cell immunity between common cold coronaviruses and SARS-CoV-2 may influence COVID-19 susceptibility. To identify cross-reactive CD8 T cell epitopes, we analyzed responses to 21 homologous SARS-CoV-2 replicase peptides in 177 people living with HIV (PLWH) on antiretroviral therapy, of which 133 did not have prior SARS-CoV-2 infection. Replicase peptides induced IFN-γ responses in 63% of the SARS-CoV-2-naïve individuals and in 73% of individuals with prior SARS-CoV-2-infection. We could define several cross-reactive epitopes, including the HLA-B∗35:03 restricted CoV-YL8, and characterized a CoV-YL8-specific T cell receptor cloned from a SARS-CoV-2 seronegative individual. Analysis of the association between HLA-I alleles and SARS-CoV-2 infections over a 16-months period revealed that in a cohort of 452 PLWH, HLA-B∗35:03 and C∗07 were underrepresented in the 55 persons with a history of SARS-CoV-2 infection while HLA-B∗35:01 and HLA-C∗04 were associated with a higher infection rate. Taken together, our study suggests an HLA-I-mediated effect of common cold coronaviruses on SARS-CoV-2 immunity.

Antiretroviral therapy (ART) inhibits Human Immunodeficiency Virus (HIV) replication to maintain undetectable viral loads in people living with HIV, but does not result in a cure. Due to the significant challenges of lifelong ART for many, there is strong interest in therapeutic strategies that result in cure. Recent clinical trials have shown that administration of broadly neutralizing antibodies (bnAbs) when there is some viremia can lead to ART-free viral control in some people; however, the underlying mechanisms are unclear. Our computational modeling shows that bnAbs administered in the presence of some viremia promote the evolution of autologous antibodies (aAbs) that target diverse epitopes of HIV spike proteins. This "net" of polyclonal aAbs could confer control since evasion of this response would require developing mutations in multiple epitopes. Our results provide a common mechanistic framework underlying recent clinical observations upon bnAb/ART therapy, and they should also motivate and inform new trials.

An HIV-1 vaccine is long overdue. Although vaccine research focuses on the induction of broadly neutralising antibodies, challenging infections such as HIV-1 could require parallel induction of protective T cells. It is important to recognise that not all T cells contribute to protection equally. Previously, we developed a T-cell immunogen-based bivalent mosaic vaccine, HIVconsvX, delivered by vaccine vectors ChAdOx1 and modified vaccinia Ankara. In this study, we tested the HIVconsvX vaccine regimen for the first time in humans. Other ongoing trials will assess the contribution of the vaccine-induced killer T cells to the control of HIV-1.

HIV-CORE 005.2 was an open-label, dose-escalation, first-in-human, phase 1 trial done at the Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK. Eligible participants were healthy volunteers aged 18-65 years living without HIV-1 and at a low likelihood of acquiring it. Because it was the first administration of ChAdOx1.tHIVconsv1 (C1) to humans, participants were assigned stepwise to two groups. Volunteer group 1 received a low dose of C1 on enrolment. Following a satisfactory safety review 7 days after vaccination, volunteer group 2 received a full dose of C1 boosted by vaccines MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4) 4 weeks later in regimen C1-M3M4 and were followed up until day 140. Focusing on the full vaccine doses in group 2, the primary outcome was the local and systemic safety of the vaccine. The secondary outcome was the frequency and breadth of epitope recognition by vaccine-induced T cells determined by IFN-γ ELISPOT assay using peripheral blood mononuclear cells (PBMC) at peak (1 and 2 weeks after the M3M4 boost) and at the end of the study, assessed against volunteer's pre-vaccination levels. The HIV-CORE 005.2 trial is registered at ClinicalTrials.gov (NCT04586673) and is closed.

Between July 3, 2021, and Aug 3, 2022, 13 participants were recruited and assigned to group 1 (n=3) and group 2 (n=10). Low-dose C1 was safe and well tolerated in group 1, and all three vaccine components were well tolerated in volunteer group 2. There were no serious adverse events. Local and systemic reactogenicities were consistent with intramuscular needle administration of immunogenic substances. All volunteers responded, and their vaccine-elicited T-cell frequencies peaked at a median of 4433 (IQR 2750-5820) IFN-γ spot-forming units per 106 PBMC and recognised a median of 9 (IQR 9-10) peptide pools out of 10, indicating that the responses were broadly specific and each vaccine recipient targeted at least nine epitopes on HIV-1. These frequencies were 7·4 times lower by day 140 (ie, 3 months later). T cells proliferated upon antigen re-exposure and displayed multiple effector functions, recognised variant epitopes, and inhibited HIV-1 from the four major global clades A, B, C, and D.

These results inform and support a programme of clinical evaluations of the HIVconsvX T-cell vaccines together with other cutting-edge tools for HIV-1 cure and prevention such as latency reactivating agents, passively infused combinations of broadly neutralising antibodies, and active Env-based vaccines or immunomodulators.

EU Horizon 2020 Research and Innovation programme, Medical Research Council and Foreign Commonwealth and Development Office Concordat agreement, European and Developing Countries Clinical Trials Partnership, National Institute for Health Research Oxford Biomedical Research Centre, and IAVI.

To summarize the heterogeneity in the elite controllers population with the aim to identify a compatible profile with a persistent HIV remission, making distinction between persistent elite controllers, people with HIV (PWHIV) who permanently maintain virological control in the absence of antiretroviral treatment (ART), and transient elite controllers, PWHIV who eventually lose virological control. For this purpose, it is important to consider the mechanisms and biomarkers that have previously been associated with the maintenance and loss of the natural virological control.

Transient elite controllers, before losing virological control, exhibit a distinct metabolomic, proteomic, microRNAs (miRNA), immunological and virological profile compared to persistent elite controllers. In addition to a reduced and less polyfunctional HIV-specific T-cell response, transient elite controllers show a greater proportion of intact proviruses integrated into genic regions. In contrast, persistent elite controllers display a privileged HIV-1 reservoir profile with absence of detected intact proviruses or low proportion of clonal intact proviruses preferentially integrated into genomic features associated with HIV-1 transcriptional repression.

According to previous studies, the comprehensive characterization of persistent elite controllers might be crucial to identify other PWHIV with this distinct profile as spontaneously cured.

Elite controllers (ECs) and post-treatment controllers (PTCs) represent important models for achieving a functional cure for HIV. This review synthesizes findings from immunological, genetic, and virological studies to compare the mechanisms underlying HIV suppression in ECs and PTCs. Although ECs maintain viral control without antiretroviral therapy (ART), PTCs achieve suppression following ART discontinuation. Both groups rely on adaptive and innate immunity, host genetic factors, and characteristics of the HIV reservoir; however, they exhibit distinct immune responses and genetic profiles. These differences provide insights into strategies for sustained ART-free remission. Understanding the shared and unique mechanisms in ECs and PTCs can inform the development of novel therapeutic approaches, including immune-based therapies and genome editing, to achieve a functional cure for HIV-1.

Less than 0.5% of people living with HIV-1 are elite controllers (ECs)-individuals who maintain undetectable plasma viremia without antiretroviral therapy, despite having replication-competent viral reservoirs. While EC CD4+ T cells have been investigated for gene expression signatures associated with HIV-1 resistance, the expression and regulatory activity of transposable elements (TEs) remain unexplored. TEs can directly impact host immune responses to pathogens, including HIV-1, suggesting their activities could contribute to HIV-1 elite control. To begin testing this hypothesis, we conduct a TE-centric analysis of public multi-omics data from ECs and other populations.

We find the CD4+ T cell transcriptome and retrotranscriptome of ECs are distinct from healthy controls, from people living with HIV-1 on antiretroviral therapy, and from viremic progressors. However, there is substantial transcriptomic heterogeneity among ECs. We categorize ECs into four clusters with distinct expression and chromatin accessibility profiles of TEs and antiviral factors. Several TE families with known immuno-regulatory activity are differentially expressed among ECs. Their expression positively correlates with their chromatin accessibility in ECs and negatively correlates with the expression of their KRAB zinc-finger (KZNF) repressors. This coordinated, locus-level variation forms a network of putative cis-regulatory elements for genes involved in HIV-1 restriction.

We propose that the EC phenotype is driven in part by reduced KZNF-mediated repression of specific TE-derived cis-regulatory elements for antiviral genes, heightening their resistance against HIV-1. Our study reveals heterogeneity in the EC CD4+ T cell transcriptome, including variable expression of TEs and their KZNF controllers, that must be considered when deciphering HIV-1 control mechanisms.

While therapeutic vaccines are a promising strategy for inducing human immunodeficiency virus (HIV) control, HIV vaccines tested to date have offered limited benefit to people living with HIV. The barriers to success may include the use of vaccine platforms and/or immunogens that drive weak or suboptimal immune responses, immune escape and/or immune dysfunction associated with chronic infection despite effective antiretroviral therapy. Combining vaccines with immune modulators in a safe manner may address some of the challenges and thus increase the efficacy of therapeutic HIV vaccines. We evaluated the immunogenicity of a ChAd68/samRNA-based simian immunodeficiency virus (SIV) vaccine regimen alone and in combination with a series of immune modulators in a preclinical rhesus macaque (M. mulatta) model. The vaccine was co-delivered with the checkpoint inhibitors αPD-1 or αCTLA-4, or with a FLT3 receptor agonist (FLT3Ra) shown to differentiate and expand dendritic cells and improve T cell priming. We demonstrate that the magnitude, breadth and functionality of SIV-specific vaccine-elicited CD8+ T cell responses were enhanced by combination with either αPD-1, αCTLA-4, or FLT3Ra. Combination with FLT3Ra also expanded polyfunctional CD4+ T cell responses. Our data demonstrate enhanced and distinct shaping of vaccine-elicited immune responses by immune modulators with implications for developing a functional HIV cure.

A key research priority for developing a human immunodeficiency virus (HIV) cure strategy is to define the viral dynamics and biomarkers associated with sustained posttreatment control. The ability to predict the likelihood of sustained posttreatment control or noncontrol could minimize the time off antiretroviral therapy (ART) for those destined to be controllers and anticipate longer periods off ART for those destined to be controllers.

Mathematical modeling and machine learning were used to characterize virologic predictors of long-term virologic control, using viral kinetics data from several studies in which participants interrupted ART. Predictors of post-ART outcomes were characterized using data accumulated from the time of treatment interruption, replicating real-time data collection in a clinical study, and classifying outcomes as either posttreatment control (plasma viremia, ≤400 copies/mL at 2 of 3 time points for ≥24 weeks) or noncontrol.

Potential predictors of virologic control were the time to rebound, the rate of initial rebound, and the peak plasma viremia. We found that people destined to be noncontrollers could be identified within 3 weeks of rebound (prediction scores: accuracy, 80%; sensitivity, 82%; specificity, 71%).

Given the widespread use of analytic treatment interruption in cure-related trials, these predictors may be useful to increase the safety of analytic treatment interruption through early identification of people who are unlikely to become posttreatment controllers.

Viremic non-progressors (VNPs) represent an exceptional and uncommon subset of people with HIV-1, characterized by the remarkable preservation of normal CD4+ T cell counts despite uncontrolled viral replication-a trait reminiscent of natural hosts of simian immunodeficiency virus. The mechanisms orchestrating evasion from HIV-1 pathogenesis in human VNPs remain elusive, primarily due to the absence of integrative studies.

We implemented a novel single-cell and multiomics approach to comprehensively characterize viral, genomic, transcriptomic, and metabolomic factors driving this exceedingly rare disease phenotype in 16 VNPs and 29 HIV+ progressors.

Genetic predisposition to the VNP phenotype was evidenced by a higher prevalence of CCR5Δ32 heterozygosity, which was associated with lower levels of CCR5 expression and a lower frequency of infected cells in peripheral circulation. We also observed reduced levels of plasma markers of intestinal disruption and attenuated interferon responses in VNPs. These factors potentially drive the other phenotypic traits of immune preservation in this population, including the unaltered tryptophan metabolic profile, reduced activation of cytotoxic lymphocytes, and reduced bystander CD4+ T cell apoptosis.

In summary, our comprehensive analysis identified intricate factors collectively associated with the unique immunovirological equilibrium in VNPs, shedding light on potential avenues for therapeutic exploration in managing HIV pathogenesis.

The work was supported by funding from the Spanish Ministry of Science and Innovation and the National Institutes of Health (NIH).

HLA-B*58:01 and HLA-B*57 are protective alleles against human immunodeficiency virus type 1 (HIV-1) subtype B or C infection, whereas these HLA alleles have not been reported as protective in HIV-1 subtype AE infection. Although HLA-B*58:01-restricted and HLA-B*57-restricted HIV-1-specific CD8+ T cells have been thoroughly analyzed in subtype B or C infection, they have been only partially analyzed in subtype AE infection. We identified 6 HLA-B*58:01-restricted subtype AE epitopes in Vietnamese individuals infected with subtype AE. HLA-B*58:01-restricted T-cell responses to Gag epitopes, which may control disease progression in HLA-B*58:01+ and HLA-B*57+ individuals infected with subtype B or C, were not protective in subtype AE infection. These findings suggest that the loss of HLA-B*58:01-restricted T cells specific for some Gag epitopes and/or their reduced ability may account for the lack of protective effects conferred by HLA-B*58:01 in subtype AE infection.

The human immune system is equipped to neutralize and eliminate viruses and other foreign antigens via binding of human leukocyte antigen (HLA) molecules with foreign antigen epitopes and presenting them to T cells. HLA is highly polymorphic, resulting in subtle differences in the binding groove that influence foreign antigen binding and elimination. Here we tested the hypothesis that certain HLA alleles may promote longevity by enhanced ability to counter virus antigens that may otherwise contribute to morbidity and mortality.

We utilized high-resolution genotyping to characterize HLA and apolipoprotein E in a large sample (N = 986) of participants (469 men, 517 women) ranging in age from 24 to 90+ years old (mean age: 58.10 years) and identified 244 HLA alleles that occurred in the sample. Since each individual carries 12 classical HLA alleles (6 alleles of each Class I and Class II), we determined in silico the median predicted binding affinity for each individual (across the 12 HLA alleles) and each of 13 common viruses (Human Herpes Virus 1 [HHV1], HHV2, HHV3, HHV4, HHV5, HHV6A, HHV6B, HHV7, HHV8, human papilloma virus [HPV], human polyoma virus [JCV], human endogenous retrovirus K [HERVK], and HERVW). Next, we performed a stepwise multiple linear regression where the age of the participant was the dependent variable and the 13 median predicted HLA-virus binding affinities were the independent variables.

The analyses yielded only one statistically significant effect-namely, a positive association between age and HERVK (P = 0.005). Furthermore, we identified 13 HLA alleles (9 HLA-I and 4 HLA-II) that occurred at greater frequency in very old individuals (age ≥90 years) as compared to younger individuals. Remarkably, for those 13 alleles, the predicted binding affinities were significantly higher for HERVK than for the other viruses (P < 0.001). ApoE genotypes did not differ significantly between older and younger groups.

Taken together, the results showed that HLA-HERVK binding affinity is a robust predictor of longevity and that HLA alleles that bind with high affinity to HERVK were enriched in very old individuals. The findings of the present study highlight the influence of interactions between host immunogenetics and virus exposure on longevity and suggest that specific HLA alleles may promote longevity via enhanced immune response to specific common viruses, notably HERVK.

T cells mediate pathogenesis of several autoimmune disorders by recognizing self-epitopes presented on Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) complex. The majority of autoantigens presented to T cells in various autoimmune disorders are not known, which has impeded autoantigen identification. Recent advances in immunopeptidomics have started to unravel the repertoire of antigenic epitopes presented on MHC. In several autoimmune diseases, immunopeptidomics has led to the identification of novel autoantigens and has enhanced our understanding of the mechanisms behind autoimmunity. Especially, immunopeptidomics has provided key evidence to explain the genetic risk posed by HLA alleles. In this review, we shed light on how immunopeptidomics can be leveraged to discover potential autoantigens. We highlight the application of immunopeptidomics in Type 1 Diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Rheumatoid Arthritis (RA). Finally, we highlight the practical considerations of implementing immunopeptidomics successfully and the technical challenges that need to be addressed. Overall, this review will provide an important context for using immunopeptidomics for understanding autoimmunity.

We have reanalyzed the genomic data from the International Collaboration for the Genomics of HIV (ICGH), focusing on HIV-1 Elite Controllers (EC).

A genome-wide association study (GWAS) was performed, comparing 543 HIV-1 EC individuals with 3,272 uninfected controls (CTR) of European ancestry. 8 million single nucleotide polymorphisms (SNPs) and HLA class I and class II gene alleles were imputed to compare EC and CTR.

Two thousand six hundred twenty-six SNPs were associated with EC (p<5.10-8), all located within the Major Histocompatibility Complex (MHC) region. Stepwise regression analysis narrowed this list to 17 SNPs. In parallel, 22 HLA class I and II alleles were associated with EC. Through meticulous mapping of the LD between all identified signals and employing reciprocal covariate analyses, we delineated a final set of 6 independent SNPs and 3 HLA class I gene alleles that accounted for most of the associations observed with EC. Our study revealed the presence of cumulative haploblock effects (SNP rs9264942 contributing to the HLA-B*57:01 effect) and that several HLA allele associations were in fact caused by SNPs in linkage disequilibrium (LD). Upon investigating SNPs in LD with the selected 6 SNPs and 3 HLA class I alleles for their impact on protein function (either damaging or differential expression), we identified several compelling mechanisms potentially explaining EC among which: a multi-action mechanism of HLA-B*57:01 involving MICA mutations and MICB differential expression overcoming the HIV-1 blockade of NK cell response, and overexpression of ZBTB12 with a possible anti-HIV-1 effect through HERV-K interference; a deleterious mutation in PPP1R18 favoring viral budding associated with rs1233396.

Our results show that MHC influence on EC likely extends beyond traditional HLA class I or class II allele associations, encompassing other MHC SNPs with various biological impacts. They point to the key role of NK cells in preventing HIV-1 infection. Our analysis shows that HLA-B*57:01 is indeed associated with partially functional MICA/MICB proteins which could also explain this marker's involvement in other diseases such as psoriasis. More broadly, our findings suggest that within any HLA class I and II association in diseases, there may exist distinct causal SNPs within this crucial, gene-rich, and LD-rich MHC region.

This review focuses on the viral and immune factors influencing HIV posttreatment control (PTC), a rare condition where individuals maintain viral suppression after discontinuing antiretroviral therapy (ART).

Studies demonstrate that early ART initiation leads to smaller HIV reservoirs and delayed viral rebound in PTCs. Virologically, PTCs harbor smaller HIV reservoirs and show lower levels of reservoir transcriptional activity compared with posttreatment noncontrollers. Immunologically, PTCs exhibit distinct T-cell dynamics, with reduced CD4+ and CD8+ T-cell activation and exhaustion, enhanced natural killer (NK) cell activity, and enhanced proliferative responses of HIV-specific CD8+ T cells post-ART interruption. Additionally, humoral immunity, particularly the development of autologous neutralizing antibodies (aNAbs), plays a role in viral control, though broadly neutralizing antibodies (bnAbs) are rare.

The mechanisms behind posttreatment control are multifactorial, involving virological and immunological factors. Early ART initiation, a smaller and less transcriptionally active HIV reservoir, and immune responses including proliferative T-cell activity and NK cell function are key contributors to achieving ART-free HIV remission.

HIV cure has been reported for five individuals who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) with cells from CCR5Δ32 homozygous donors. By contrast, viral rebound has occurred in other people living with HIV who interrupted antiretroviral treatment after undergoing allo-HSCT, with cells mostly from wild-type CCR5 donors. Here we report the case of a male individual who has achieved durable HIV remission following allo-HSCT with cells from an unrelated HLA-matched (9 of 10 matching for HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 alleles) wild-type CCR5 donor to treat an extramedullary myeloid tumor. To date, plasma viral load has remained undetectable for 32 months after the interruption of antiretroviral treatment. Treatment with ruxolitinib has been maintained during this period to treat chronic graft-versus-host disease. Low levels of proviral DNA were detected sporadically after allo-HSCT, including defective but not intact HIV DNA. No virus could be amplified in cultures of CD4+ T cells obtained after antiretroviral treatment interruption, while CD4+ T cells remained susceptible to HIV-1 infection in vitro. Declines in HIV antibodies and undetectable HIV-specific T cell responses further corroborate the absence of viral rebound after antiretroviral treatment interruption. These results suggest that HIV remission could be achieved in the context of allo-HSCT with wild-type CCR5.

To review the role of innate immune cells in shaping the viral reservoir and maintenance of long-term viral control of spontaneous Elite and Viremic HIV controllers.

HIV controllers exhibit a smaller and transcriptionally suppressed viral reservoir. Different studies report that early responses from innate cells play a pivotal role in this reservoir configuration. NK cells, particularly those with cytotoxic activity and polyfunctional monocytes, have been linked to viral control, and DCs may contribute through early viral sensing and activation of adaptive responses. In some cases, cytotoxic NK cells appeared before HIV-specific CD8 + T cells, underscoring their importance in early viral suppression. Innate immune cells, including NK cells, monocytes, DCs, and γδ T-cells, are crucial in shaping the viral reservoir in HIV controllers. Early, robust innate responses may help to maintain long-term viral suppression and offer insights into potential therapeutic approaches.

Following success in cancer immunotherapy, immune checkpoint blockade is emerging as an exciting potential treatment for some infectious diseases, specifically two chronic viral infections, HIV and hepatitis B. Here, we will discuss the function of immune checkpoints, their role in infectious disease pathology, and the ability of immune checkpoint blockade to reinvigorate the immune response. We focus on blockade of programmed cell death 1 (PD-1) to induce durable immune-mediated control of HIV, given that anti-PD-1 can restore function to exhausted HIV-specific T cells and also reverse HIV latency, a long-lived form of viral infection. We highlight several key studies and future directions of research in relation to anti-PD-1 and HIV persistence from our group, including the impact of immune checkpoint blockade on the establishment (AIDS, 2018, 32, 1491), maintenance (PLoS Pathog, 2016, 12, e1005761; J Infect Dis, 2017, 215, 911; Cell Rep Med, 2022, 3, 100766) and reversal of HIV latency (Nat Commun, 2019, 10, 814; J Immunol, 2020, 204, 1242), enhancement of HIV-specific T cell function (J Immunol, 2022, 208, 54; iScience, 2023, 26, 108165), and investigating the effects of anti-PD-1 and anti-CTLA-4 in vivo in people with HIV on ART with cancer (Sci Transl Med, 2022, 14, eabl3836; AIDS, 2021, 35, 1631; Clin Infect Dis, 2021, 73, e1973). Our future work will focus on the impact of anti-PD-1 in vivo in people with HIV on ART without cancer and potential combinations of anti-PD-1 with other interventions, including therapeutic vaccines or antibodies and less toxic immune checkpoint blockers.

This study aims to understand the impact of early antiretroviral therapy (ART) on HIV-specific T-cell responses measured after treatment interruption, which may inform strategies to deliver ART-free immune-mediated viral suppression. HIV-specific T-cell immunity was analysed using gamma interferon enzyme-linked immunospot assays in two studies. SPARTAC included individuals with primary HIV infection randomised to 48 weeks of ART (n = 24) or no immediate therapy (n = 37). The PITCH (n = 7) cohort started antiretroviral therapy in primary infection for at least one year, followed by TI. In SPARTAC, participants treated in PHI for 48 weeks followed by TI for 12 weeks, and those who remained untreated for 60 weeks made similar HIV Gag-directed responses (both magnitude and breadth) at week 60. However, the treated group made a greater proportion of novel HIV Gag-directed responses by Week 60, suggestive of a greater reserve to produce new potentially protective responses. In the more intensively followed PITCH study, 6/7 participants showed dominant Gag and/or Pol-specific responses post-TI compared with pre-TI. Although early ART in PHI was not associated with major differences in HIV-specific immunity following TI compared with untreated participants, the potential to make more new Gag-directed responses warrants further investigation as this may inform strategies to achieve ART-free control.

The accurate determination of an individual's unique human leukocyte antigen (HLA) allele holds important significance in evaluating the risk associated with autoimmune and infectious diseases, such as human immunodeficiency virus (HIV) infection. Several allelic variants within the HLA system have been linked to either increased protection or susceptibility in the context of infectious and autoimmune diseases. This study aimed to determine the frequency and association of HLA alleles between people living with HIV (PLHIV) as the case group and Peruvian individuals without HIV with high-risk behaviors of sexually transmitted diseases as the control group. Whole exome sequencing (WES) was used to determine high-resolution HLA allelotypes using the OptiType and arcas HLA tools. The HLA alleles present in HLA classes I (A, B, and C loci) and II (DPB1, DQA1, DQB1, and DRB1 loci) were determined in a cohort of 59 PLHIV (cases) and 44 individuals without HIV (controls). The most frequent HLA alleles were A*02:01, DPB1*04:02, and DQB1*03:419 at 36%, 30%, and 28% prevalence in general population. We found that C*07:01 (p = 0.0101; OR = 10.222, 95% IC: 1.40-74.55), DQA1*03:02 (p = 0.0051; OR = 5.297, 95% IC: 1.48-19.02), and DRB1*09:01 (p = 0.0119; OR = 4.788, 95% IC: 1.39-16.44) showed an association with susceptibility to HIV infection, while DQB1*03:419 (p = 0.0478; OR = 0.327, 95% IC: 0.11-0.96) was associated with protection from HIV infection. Our findings contribute to the knowledge of HLA allele diversity in the Peruvian population (around 70% South American indigenous ancestry) lays the groundwork for further valuable large-scale use of HLA typing and offers a novel association with HIV infection that is relevant to vaccine studies.

Human leukocyte antigen (HLA) genes are associated with a variety of diseases, yet the direct typing of HLA alleles is both time-consuming and costly. Consequently, various imputation methods leveraging sequential single nucleotide polymorphisms (SNPs) data have been proposed, employing either statistical or deep learning models, such as the convolutional neural network (CNN)-based model, DEEP*HLA. However, these methods exhibit limited imputation efficiency for infrequent alleles and necessitate a large size of reference dataset. In this context, we have developed a Transformer-based model to HLA allele imputation, named "HLA Reliable IMpuatioN by Transformer (HLARIMNT)" designed to exploit the sequential nature of SNPs data. We evaluated HLARIMNT's performance using two distinct reference panels; Pan-Asian reference panel (n = 530) and Type 1 Diabetes genetics Consortium (T1DGC) reference panel (n = 5225), alongside a combined panel (n = 1060). HLARIMNT demonstrated superior accuracy to DEEP*HLA across several indices, particularly for infrequent alleles. Furthermore, we explored the impact of varying training data sizes on imputation accuracy, finding that HLARIMNT consistently outperformed across all data size. These findings suggest that Transformer-based models can efficiently impute not only HLA types but potentially other gene types from sequential SNPs data.

The human leukocyte antigen (HLA) system plays a pivotal role in the immune response to viral infections, mediating the presentation of viral peptides to T cells and influencing both the strength and specificity of the host immune response. Variations in HLA genotypes across individuals lead to differences in susceptibility to viral infection and severity of illness. This study uses observations from the early phase of the COVID-19 pandemic to explore how specific HLA class I molecules affect clinical responses to SARS-CoV-2 infection. By analyzing paired high-resolution HLA types and viral genomic sequences from 60 patients, we assess the relationship between predicted HLA class I peptide binding repertoires and infection severity as measured by the sequential organ failure assessment score. This approach leverages functional convergence across HLA-C alleles to identify relationships that may otherwise be inaccessible due to allelic diversity and limitations in sample size. Surprisingly, our findings show that severely symptomatic infection in this cohort is associated with disproportionately abundant binding of SARS-CoV-2 structural and non-structural protein epitopes by patient HLA-C molecules. In addition, the extent of overlap between a given patient's predicted HLA-C and HLA-A peptide binding repertoires correlates with worse prognoses in this cohort. The findings highlight immunologic mechanisms linking HLA-C molecules with the human response to viral pathogens that warrant further investigation.

Variation within the non-coding genome may influence the regulation and expression of important genes involved in immune control such as the human leukocyte antigen (HLA) system. Class I and Class II HLA molecules are essential for peptide presentation which is required for T lymphocyte activation. Single nucleotide polymorphisms within non-coding regions of HLA Class I and Class II genes may influence the expression of these genes by affecting the binding of transcription factors and chromatin modeling molecules. Furthermore, an interplay between genetic and epigenetic factors may also influence HLA expression. Epigenetic factors such as DNA methylation and non-coding RNA, regulate gene expression without changing the DNA sequence. However, genetic variation may promote or allow genes to escape regulation by epigenetic factors, resulting in altered expression. The HLA system is central to most diseases, therefore, understanding the role of genetics and epigenetics on HLA regulation will tremendously impact healthcare. The knowledge gained from these studies may lead to novel and cost-effective diagnostic approaches and therapeutic interventions. This review discusses the role of non-coding variants on HLA regulation. Furthermore, we discuss the interplay between genetic and epigenetic factors on the regulation of HLA by evaluating literature based on polymorphisms within DNA methylation and miRNA regulatory sites within class I and Class II HLA genes. We also provide insight into the importance of the HLA non-coding genome on disease, discuss ethnic-specific differences across the HLA region and provide guidelines for future HLA studies.

High HIV viral loads (VL) are associated with increased morbidity, mortality, and on-going transmission. HIV controllers maintain low VLs in the absence of antiretroviral therapy (ART). We previously used a massively multiplexed antibody profiling assay (VirScan) to compare antibody profiles in HIV controllers and persons living with HIV (PWH) who were virally suppressed on ART. In this report, we used VirScan to evaluate whether antibody reactivity to specific HIV targets and broad reactivity across the HIV genome was associated with VL and controller status 1-2 years after infection.

Samples were obtained from participants who acquired HIV infection in a community-randomized trial in Africa that evaluated an integrated strategy for HIV prevention (HPTN 071 PopART). Controller status was determined using VL and antiretroviral (ARV) drug data obtained at the seroconversion visit and 1 year later. Viremic controllers had VLs <2,000 copies/mL at both visits; non-controllers had VLs >2,000 copies/mL at both visits. Both groups had no ARV drugs detected at either visit. VirScan testing was performed at the second HIV-positive visit (1-2 years after HIV infection).

The study cohort included 13 viremic controllers and 64 non-controllers. We identified ten clusters of homologous peptides that had high levels of antibody reactivity (three in gag, three in env, two in integrase, one in protease, and one in vpu). Reactivity to 43 peptides (eight unique epitopes) in six of these clusters was associated with lower VL; reactivity to six of the eight epitopes was associated with HIV controller status. Higher aggregate antibody reactivity across the eight epitopes (more epitopes targeted, higher mean reactivity across all epitopes) and across the HIV genome was also associated with lower VL and controller status.

We identified HIV antibody targets associated with lower VL and HIV controller status 1-2 years after infection. Robust aggregate responses to these targets and broad antibody reactivity across the HIV genome were also associated with lower VL and controller status. These findings provide novel insights into the relationship between humoral immunity and viral containment that could help inform the design of antibody-based approaches for reducing HIV VL.

Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.

Elite controllers (ECs), a unique group of people with HIV (PWH), exhibit remarkable control of viral replication in the absence of antiretroviral therapy. In this study, we comprehensively characterized the NK cell repertoire in ECs after long-term viral control. Phenotypic profiling of NK cells revealed profound differences compared with other PWH, but marked similarities to uninfected individuals, with a distinctive prevalence of NKG2C+CD57+ memory-like NK cells. Functional analyses indicated that ECs had limited production of functional molecules upon NK stimulation and consequently reduced natural cytotoxicity against non-HIV target cells. Importantly, ECs showed an exceptional ability to kill primary HIV-infected cells by the antibody-dependent cell cytotoxicity adaptive mechanism, which was achieved by a specific memory-like NK population expressing CD16, NKG2A, NKG2C, CD57, and CXCR3. In-depth single-cell RNA-seq unveiled a unique transcriptional signature in these NK cells linked to increased cell metabolism, migration, chemotaxis, effector functions, cytokine secretion, and antiviral response. Our findings underscore a pivotal role of NK cells in the immune control of HIV and identify specific NK cells as emerging targets for immunotherapies.

Exceptional elite controllers represent an extremely rare group of people with HIV-1 (PWH) who exhibit spontaneous, high-level control of viral replication below the limits of detection in sensitive clinical monitoring assays and without disease progression in the absence of antiretroviral therapy for prolonged periods, frequently exceeding 25 years. Here, we discuss the different cases that have been reported in the scientific literature, their unique genetic, virological, and immunological characteristics, and their relevance as the best model for the functional cure of HIV-1.

Africa remains significantly underrepresented in high-resolution Human Leukocyte Antigen (HLA) data, despite being one of the most genetically diverse regions in the world. This critical gap in genetic information poses a substantial barrier to HLA-based research on the continent. In this study, Class I HLA data from Eastern and Southern African populations were analysed to assess genetic diversity across the region. We examined allele and haplotype frequency distributions, deviations from Hardy-Weinberg Equilibrium (HWE), linkage disequilibrium (LD), and conducted neutrality tests of homozygosity across various populations. Additionally, the African HLA data were compared to those of Caucasian and African American populations using the Jaccard index and multidimensional scaling (MDS) methods. The study revealed that South African populations exhibited 50.4% more genetic diversity within the Class I HLA region compared to other African populations. Zambia showed an estimated 36.5% genetic diversity, with Kenya, Rwanda and Uganda showing 35.7%, 34.2%, and 31.1%, respectively. Furthermore, an analysis of in-country diversity among different tribes indicated an average Class I HLA diversity of 25.7% in Kenya, 17% in Rwanda, 2.8% in South Africa, 13.6% in Uganda, and 6.5% in Zambia. The study also highlighted the genetic distinctness of Caucasian and African American populations compared to African populations. Notably, the differential frequencies of disease-promoting and disease-preventing HLA alleles across these populations emphasize the urgent need to generate high-quality HLA data for all regions of Africa and its major ethnic groups. Such efforts will be crucial in enhancing healthcare outcomes across the continent.

Efforts towards an effective HIV-1 vaccine have remained mainly unsuccessful. There is increasing evidence for a potential role of HLA-C-restricted CD8+ T cell responses in HIV-1 control, including our recent report of HLA-C*03:02 among African children. However, there are no documented optimal HIV-1 CD8+ T cell epitopes restricted by HLA-C*03:02; additionally, the structural influence of HLA-C*03:02 on epitope binding is undetermined. Immunoinformatics approaches provide a fast and inexpensive method to discover HLA-restricted epitopes. Here, we employed immunopeptidomics to identify HLA-C*03:02 CD8+ T cell epitopes. We identified a clade-specific Gag-derived GY9 (GTEELRSLY) HIV-1 p17 matrix epitope potentially restricted to HLA-C*03:02. Residues E62, T142, and E151 in the HLA-C*03:02 binding groove and positions p3, p6, and p9 on the GY9 epitope are crucial in shaping and stabilizing the epitope binding. Our findings support the growing evidence of the contribution of HLA-C molecules to HIV-1 control and provide a prospect for vaccine strategies.

Immunogenetic studies have shown that specific HLA-B residues (67, 70, 97, and 156) mediate the impact of HLA class I on HIV infection, but the molecular basis is not well understood. Here we evaluate the function of these residues within the protective HLA-B∗5701 allele. While mutation of Met67, Ser70, and Leu156 disrupt CD8+ T cell recognition, substitution of Val97 had no significant impact. Thermal denaturation of HLA-B∗5701-peptide complexes revealed that Met67 and Leu156 maintain HLA-peptide stability, while Ser70 and Leu156 facilitate T cell receptor (TCR) interactions. Analyses of existing structures and structural models suggested that Val97 mediates HLA-peptide binding to inhibitory KIR3DL1 molecules, which was confirmed by experimental assays. These data thereby demonstrate that the genetic basis by which host immunity impacts HIV outcomes occurs by modulating HLA-B-peptide stability and conformation for interaction with TCR and killer immunoglobulin receptor (KIR) molecules. Moreover, they indicate a key role for epitope specificity and HLA-KIR interactions to HIV control.