Elite Controllers Research Articles

Long-term non-progression in children living with HIV: estimates from international cohort data.

To estimate the probability of long-term nonprogression (LTNP) in the absence of antiretroviral treatment (ART) in children with perinatally acquired HIV, and the impact of LTNP definitions on these estimates. Analysis of longitudinal routine care data (follow-up to 2016) collected through a collaboration of cohorts of children in routine HIV care across Europe and Thailand. LTNP was defined as reaching age 8 years without disease progression (defined as an AIDS diagnosis or immunosuppression based on WHO immunosuppression-for-age thresholds, age-adjusted CD4+z-scores or CD4+ counts). ART initiation was treated as a competing risk (children initiating ART before age 8 were not considered to have LTNP). We included children born domestically in six national HIV cohorts (n = 2481). Additional analyses included domestic-born children enrolled in national cohorts in infancy (aged <12 months, n = 1144, six cohorts), or all domestic-born children in national and nonnational cohorts (n = 4542, 18 cohorts). Results were stratified by birth year. Among children born domestically in national cohorts in 2004-2007, the probability [95% confidence interval (CI)] of LTNP at age 8 years was 10% (6-15%) based on WHO immunosuppression-for-age criteria. This was lower for children born earlier when ART use was less frequent. Results were similar using other immunosuppression thresholds. Estimates were lower when restricted to domestic-born children in national cohorts enrolled in infancy, and higher when including all domestic-born children. Up to 10% of children born during 2004-2007 had LTNP at age 8. Our findings may help identify participants with LTNP for research into posttreatment control and HIV cure.

Impact of unique host genetic variants in the HIV life cycle, differentiates the long-term non-progressors and rapid progressors in South Indian females

Impact of unique host genetic variants in the HIV life cycle, differentiates the long-term non-progressors and rapid progressors in South Indian females

‘A Culmination of Many Factors’: Opportunities, Arenas, and Challenges to Malaysia’s Dominant Regime

ABSTRACT The victory of the opposition Pakatan Harapan (PH) coalition in the 2018 Malaysian election was a political earthquake, as it saw the end of over 60 years of rule by the dominant Barisan Nasional (BN) regime. Victory for the coalition resulted from a number of factors, as opponents came together to craft a strategy that was able to overcome an extensive system of social control that the BN regime had built and reinforced during its time in power. The aim of the paper is to examine how civil society and political actors were able to craft a coalition that was sufficiently robust to challenge the dominant position of the BN regime. In doing so, the findings point to the role and impact of civil society in a context of weakening elite control. Drawing on interviews conducted with civil society actors shortly after the election, the paper identifies the key actors involved, how they formulated claims, and the importance of connecting the protest and electoral arenas to achieve their ends.

P-551. The Effects of Antiretroviral Therapy on Immune Activation, Inflammation, Cellular Changes and Clinical Outcomes in Elite Controllers

Abstract Background Elite controllers are people living with HIV (PLWH) who maintain their HIV viral load (VL) &amp;lt; 50 copies/mL without antiretroviral therapy (ART). Viremic controllers are persons who have HIV who are able to keep their VL &amp;lt; 2000 copies/mL without ART. Current published data does not clearly define the benefits of ART nor the adverse effects of ART in elite controllers. Evaluation of the effects of ART on immune activation, inflammatory markers, mitochondrial and cellular function in elite controllers can better inform utilization of ART in this group. Methods Four PLWH—3 elite controllers and 1 viremic controller— were enrolled from our HIV academic center clinic. Participants were women aged 45 to 60 years old who were diagnosed with HIV for 5 to 35 years. After shared decision making with their primary care provider, 2 of the 4 participants were started on ART, one on Triumeq and the other on Cabenuva. Participants were followed from 0 to 12 months. At each visit, routine standard of care labs, as well as inflammatory lab markers IL-6 and CRP were drawn. We assessed their mitochondrial function measuring mitochondrial membrane potential, mitochondrial DNA (mtDNA) deletions, apoptosis, and reactive oxygen species (ROS) production. Results Compared to baseline levels, inflammatory markers IL-6 and CRP both decreased at 12-months in participants started on ART (E2 and E3), whereas these markers increased in controls (E1 and E4) (Figure 1). All participants have increased apoptosis and ROS production at 12-months compared to baseline (Figure 2). At the 12-months visit, participants in the ART group (E2 and E3) showed elevated levels of mtDNA deletion, apoptosis, ROS production, and a reduction in mitochondrial membrane potential (Figure 2). Conclusion From our small cohort, the observed IL-6 and CRP decrease suggest decreased inflammation at one year after elite controllers start ART. However, decreased mitochondrial function was also noted in those on ART, which suggests possible early signs of ART toxicity. This preliminary data emphasizes the need for further studies to better understand the risk-benefit of initiating ART in elite controllers, including markers for cellular inflammatory markers. Disclosures Brinda Emu, MD, Genentech/Roche: Advisor/Consultant|Theratechologies: Advisor/Consultant

Effect of antiretroviral therapy on the mortality of HIV-1 infection long-term non-progressors: a cohort study

BackgroundThe study aims to investigate the demographic characteristics, the variations in their immune status, and mortality risk among HIV-1 infection long-term non-progressors (LTNP).MethodsEligible LTNP and typical progressors (TP) were recruited in Guangxi by December 2018. Participants were followed up until December 2022, monitoring ART status, CD4+ T cell counts, and survival/death outcomes. Multivariate logistic, Cox regression, and Kaplan-Meier method were employed to scrutinize associated factors and mortality risk of LTNP.ResultsA total of 212 LTNP and 390 TP were included. LTNP cohort predominantly comprised males (84.43%), those diagnosed with HIV at age ≤ 40 years (93.87%), and those infected through injection drug use (59.91%). The mortality rate of LTNP were lower than TP (12.74% vs. 27.18%). TP had a higher mortality risk compared to LTNP (adjusted hazard ratio [aHR] = 4.051, 95% CI: 2.284–7.186, P < 0.001). The mortality risk was also elevated in the ART-naïve group versus the ART-experienced ones (aHR = 3.943, 95%CI: 2.658–5.850, P < 0.001). Notably, the CD4/CD8 ratio in the LTNP group did not fully recover (< 1.0) despite ART. However, LTNP with ART-experienced had a significantly lower mortality risk compared to ART-naïve LTNP group (Log-rank: P = 0.003).ConclusionsART effectively restores and maintains normal CD4+ T cell levels among LTNP, thereby decreasing mortality risk. Nonetheless, the CD4/CD8 ratio in LTNP exhibits incompletely recovered post-ART. These findings provide a scientific foundation for promoting ART in LTNP population.

Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS

Deep analysis of the major histocompatibility complex genetic associations using covariate analysis and haploblocks unravels new mechanisms for the molecular etiology of Elite Control in AIDS

The Proviral Reservoirs of Human Immunodeficiency Virus (HIV) Infection.

Human Immunodeficiency Virus (HIV) proviral reservoirs are cells that harbor integrated HIV proviral DNA within their nuclear genomes. These cells form a heterogeneous group, represented by peripheral blood mononuclear cells (PBMCs), tissue-resident lymphoid and monocytic cells, and glial cells of the central nervous system. The importance of studying the properties of proviral reservoirs is connected with the inaccessibility of integrated HIV proviral DNA for modern anti-retroviral therapies (ARTs) that block virus reproduction. If treatment is not effective enough or is interrupted, the proviral reservoir can reactivate. Early initiation of ART improves the prognosis of the course of HIV infection, which is explained by the reduction in the proviral reservoir pool observed in the early stages of the disease. Different HIV subtypes present differences in the number of latent reservoirs, as determined by structural and functional differences. Unique signatures of patients with HIV, such as elite controllers, have control over viral replication and can be said to have achieved a functional cure for HIV infection. Uncovering the causes of this phenomenon will bring humanity closer to curing HIV infection, potential approaches to which include stem cell transplantation, clustered regularly interspaced short palindromic repeats (CRISPR)/cas9, "Shock and kill", "Block and lock", and the application of broad-spectrum neutralizing antibodies (bNAbs).

Impact of Anti-CD4 Autoantibodies on Immune Reconstitution in People With Advanced Human Immunodeficiency Virus.

Despite suppressive antiretroviral therapy (ART), 15%-30% of people with human immunodeficiency virus (HIV) experience a limited recovery of CD4 T cells. Although autoantibodies against the CD4 receptor have previously been identified in people with HIV (PWH), little is known about their longitudinal impact on CD4 T-cell reconstitution. Anti-CD4 autoantibodies were evaluated by the fluid-phase luciferase immunoprecipitation systems immunoassay in ART-naive people with advanced HIV (CD4 count ≤100 cells/µL), PWH with CD4 count >200 cells/µL, long-term nonprogressors, people with idiopathic CD4 lymphopenia, people with autoimmune lymphoproliferative syndrome, and healthy volunteers without HIV. In the participants with advanced HIV, we assessed the association of anti-CD4 autoantibodies at ART initiation with CD4 recovery over a median follow-up of 192 weeks. Anti-CD4 autoantibodies were identified in 29% (61/210) of ART-naive participants with advanced HIV but were absent in people without HIV. Female PWH showed a 4-fold higher prevalence (P < .001) of anti-CD4 autoantibodies compared to males. After ART initiation, people with advanced HIV with anti-CD4 autoantibodies exhibited an overall slower rate of CD4 reconstitution (5.8 vs 6.6 cells/µL/month, P = .007) and lower week 192 CD4 count (268 vs 355 cells/µL, P = .037). Incidental, clinically indicated immunosuppressive therapy in these participants was associated with an improved rate of CD4 reconstitution (P = .0019) and higher week 192 CD4 count (551 vs 268 cells/µL, P = .019). People with advanced HIV harboring anti-CD4 autoantibodies at ART initiation demonstrated a slower rate and extent of CD4 reconstitution after 4 years. Incidental immunosuppressive therapy was associated with increased CD4 counts in these participants.

Persistent elite controllers as the key model to identify permanent HIV remission.

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.

High KIR diversity in Uganda and Botswana children living with HIV.

Killer-cell immunoglobulin-like receptors (KIRs) are essential components of the innate immune system found on the surfaces of natural killer (NK) cells. The KIRs encoding genes are located on chromosome 19q13.4 and are genetically diverse across populations. KIRs are associated with various disease states including HIV progression, and are linked to transplantation rejection and reproductive success. However, there is limited knowledge on the diversity of KIRs from Uganda and Botswana HIV-infected paediatric cohorts, with high endemic HIV rates. We used next-generation sequencing technologies on 312 (246 Uganda, 66 Botswana) samples to generate KIR allele data and employed customised bioinformatics techniques for allelic, allotype and disease association analysis. We show that these sample sets from Botswana and Uganda have different KIRs of different diversities. In Uganda, we observed 147 vs 111 alleles in the Botswana cohort, which had a more than 1 % frequency. We also found significant deviation towards homozygosity for the KIR3DL2 gene for both rapid (RPs) and long-term non-progressors (LTNPs)in the Ugandan cohort. The frequency of the bw4-80I ligand was also significantly higher among the LTNPs than RPs (8.9 % Vs 2.0%, P-value: 0.032). In the Ugandan cohort, KIR2DS4*001 (OR: 0.671, 95 % CI: 0.481-0.937, FDR adjusted Pc=0.142) and KIR2DS4*006 (OR: 2.519, 95 % CI: 1.085-5.851, FDR adjusted Pc=0.142) were not associated with HIV disease progression after adjustment for multiple testing. Our study results provide additional knowledge of the genetic diversity of KIRs in African populations and provide evidence that will inform future immunogenetics studies concerning human disease susceptibility, evolution and host immune responses.

6.5 – 00173 A single-infusion of CCR5 modified stem-like CD4 T cells to limit HIV/SIV persistence during ART and promote control of viremia upon ATI

6.5 – 00173 A single-infusion of CCR5 modified stem-like CD4 T cells to limit HIV/SIV persistence during ART and promote control of viremia upon ATI

Humoral immunity in HIV-1 post-treatment controllers.

Decoding the HIV-1 immune response, including its humoral arm, in post-treatment controllers (PTCs) is paramount to unveil immune correlates of viral control, which could help developing novel strategies towards HIV-1 remission. Here, we review novel findings on the humoral response to HIV-1 in PTCs. New data reveal the heterogeneity of humoral immune profiles in PTCs, principally influenced by viral exposure and dynamics. Stably aviremic PTCs, akin early ART-treated individuals, show minimal antibody B-cell response. Conversely, virally exposed PTCs develop functionally coordinated and effective humoral responses to HIV-1. They can produce antibodies cross-neutralizing heterologous HIV-1 viruses, including broadly neutralizing antibodies (bNAbs) exerting selective immune pressure. PTCs also elicit neutralizing antibodies against contemporaneous autologous viruses presumed to play a major role in sustaining viral suppression. The immune mechanisms underlying virologic control in PTCs likely involve various immune effectors. Notably, functional HIV-1 humoral responses can generate bNAbs and autologous neutralizing antibodies; however, their exact contribution to maintaining long-term control of plasma viremia and the precise mechanisms driving their induction require further investigation.

HIV-1 Elite Controllers Are Characterized by Elevated Levels of CD69-Expressing Natural Killer Cells.

HIV type 1 ((human immunodeficiency virus) HIV-1) elite controllers (ECs) are a rare subset of people living with HIV-1 (PLWH) who control viral replication in the absence of antiretroviral treatment (ART) and may provide a model for a functional cure. We investigated the role of natural killer (NK) cells in HIV-1 ECs from South Africa. Phenotypic (CD69, CD38, CD57, PD-1), functional (CD107a, IFN-γ (inferferon gamma)), and nutrient transporter profiles (glucose transporter 1, CD98) of NK cells from ECs (n = 20), viremic progressors (VPs; n = 19), PLWH on ART (n = 20), and people without HIV-1 (PWOH; n = 21) were analyzed using flow cytometry. The Kruskal-Wallis test and followed by the Mann-Whitney U test were used to determine differences among the study groups. The Spearman rank correlation coefficient was used to determine significant associations. Compared with the other study groups, the percentage of CD69-expressing NK cells was higher in ECs, whereas the percentage of CD38-expressing NK cells was higher in VPs. Percentages of CD69 + CD38 - NK cells were elevated in ECs compared with VPs ( P = 0.003), but were not different to PLWH on ART and PWOH. Differentiation, exhaustion, and metabolic profiles were not different in ECs compared with PLWH on ART and PWOH; however, NK cell function was lower than in PWOH. These findings demonstrate that NK cells from ECs have an activated, mature profile with low levels of immune exhaustion and a reduced metabolic phenotype suggesting functional competence. This insight could inform the development of novel immunotherapeutic strategies for treating HIV-1.

Unravelling the Financial Crisis of Sri Lanka: Exploring Policy Blunders

This study explored the political-economic turmoil in Sri Lanka, with a focus on policy implementation. It delved into the dynamics of autocratic governance and elite control within the country's extractive systems, which had evolved over decades. Employing a case study methodology using data from authenticated published sources, this research unveils how ill-conceived policies, orchestrated by China-backed politicians and naïve administrators, primarily triggered the economic crisis. Mismanagement, policy missteps, and corruption fueled widespread social unrest and protests, culminating in the economic downturn. These policy blunders include tax reductions, bans on fertilizer and agrochemical imports, excessive currency printing, and exchange rate manipulation.

Acute-phase innate immune responses in SIVmac239-infected Mamu-B*08+ Indian rhesus macaques may contribute to the establishment of elite control.

Spontaneous control of chronic-phase HIV/SIV viremia is often associated with the expression of specific MHC class I allotypes. HIV/SIV-specific CD8+ cytotoxic T lymphocytes (CTLs) restricted by these MHC class I allotypes appear to be critical for viremic control. Establishment of the elite controller (EC) phenotype is predictable in SIVmac239-infected Indian rhesus macaques (RMs), with approximately 50% of Mamu-B*08+ RMs and 20% of Mamu-B*17+ RMs becoming ECs. Despite extensive characterization of EC-associated CTLs in HIV/SIV-infected individuals, the precise mechanistic basis of elite control remains unknown. Because EC and non-EC viral load trajectories begin diverging by day 14 post-infection, we hypothesized that hyperacute innate immune responses may contribute to viremic control. To gain insight into the immunological factors involved in the determination of EC status, we vaccinated 16 Mamu-B*08+ RMs with Vif and Nef to elicit EC-associated CTLs, then subjected these 16 vaccinees and an additional 16 unvaccinated Mamu-B*08+ controls to repeated intrarectal SIVmac239 challenges. We then performed whole-blood transcriptomic analysis of all 32 SIVmac239-infected Mamu-B*08+ RMs and eight SIVmac239-infected Mamu-B*08 - RMs during the first 14 days of infection. Vaccination did not provide protection against acquisition, but peak and setpoint viremia were significantly lower in vaccinees relative to controls. We did not identify any meaningful correlations between vaccine-induced CTL parameters and SIVmac239 acquisition rate or chronic-phase viral loads. Ultimately, 13 of 16 vaccinees (81%) and 7 of 16 controls (44%) became ECs (viremia ≤ 10,000 vRNA copies/mL plasma for ≥ 4 weeks). We identified subsets of immunomodulatory genes differentially expressed (DE) between RM groupings based on vaccination status, EC status, and MHC class I genotype. These DE genes function in multiple innate immune processes, including the complement system, cytokine/chemokine signaling, pattern recognition receptors, and interferon-mediated responses. A striking difference in the kinetics of differential gene expression among our RM groups suggests that Mamu-B*08-associated elite control is characterized by a robust, rapid innate immune response that quickly resolves. These findings indicate that, despite the association between MHC class I genotype and elite control, innate immune factors in hyperacute SIV infection preceding CTL response development may facilitate the establishment of the EC phenotype.

The HIV-1 vpr R77Q Mutant Induces Apoptosis, G2 Cell Cycle Arrest, and Lower Production of Pro-Inflammatory Cytokines in Human CD4+ T Cells.

Acquired immunodeficiency syndrome (AIDS) occurs when HIV depletes CD4+ helper T cells. Some patients develop AIDS slowly or not at all, and are termed long-term non-progressors (LTNP), and while mutations in the HIV-1 Viral Protein R (vpr) gene such as R77Q are associated with LTNP, mechanisms for this correlation are unclear. This study examines the induction of apoptosis, cell cycle arrest, and pro-inflammatory cytokine release in the HUT78 T cell line following infection with replication-competent wild-type strain NL4-3, the R77Q mutant, or a vpr Null mutant. Our results show a significant enhancement of apoptosis and G2 cell cycle arrest in HUT78 cells infected with R77Q, but not with WT NL4-3 or the vpr Null strain. Conversely, HUT78 cells infected with the WT virus show higher levels of necrosis. We also detected lower TNF and IL-6 release after infection with R77Q vs. WT. The apoptotic phenotype was also seen in the CEM cell line and in primary CD4+ T cells. Protein expression of the R77Q vpr variant was low compared to WT vpr, but expression levels alone cannot explain these phenotypes because the Null virus did not show apoptosis or G2 arrest. These results suggest that R77Q triggers a non-inflammatory apoptotic pathway that attenuates inflammation, possibly contributing to LTNP.

THE EFFECTS OF VALACYCLOVIR ON POLYOMAVIRUS INFECTION (BKV) IN KIDNEY TRANSPLANT RECIPIENTS

Abstract Polyomavirus-associatednephropathy(PVAN) is one of the most serious infectious complications in allograft recipients, with the BK virus (BKV) being the primary etiologic agent. This study was conducted to investigate the efficacy of valacyclovir on BK virus (BKV) infection and viremia control in infected patients in Iran. This quasi-experimental study involved 21Iranian patients. All kidney transplant recipients with a confirmed diagnosis of BKV infection based on renal biopsy and PCR were administered standard therapy (reduced doses of immunosuppressive drugs) with or without valacyclovir at a one-gram dose twice daily for one month. After collecting the data, the data was analyzed using SPSS 23. The K-S test confirmed the normality of the quantitative data. Chi-square for trend, independent-t, and Fisher's exact tests were used to examine group homogeneity in terms of socio-demographic characteristics. Before the intervention, a t-test was used to compare mean scores among the groups; and repeated measures independent sample test, pair sample test, chi square test and ANOVA. The significance level of P 0.05 was considered for all tests. The mean creatinine level, mean GFR(Glomerular Filtration Rate) level, and median viral load in the serum were not significantly different between the two groups at the time of graft rejection diagnosis. One month after treatment, the serum viral load decreased in 90.9% of patients in the intervention group and 50% of patients in the control group, with the difference being statistically significant(p=0.038). Also, in the two-month review, the results showed that the reduction of the virus serum load level was observed in 81.8% of patients in the intervention group and 40% of patients in the control group, and this difference was statistically significant (p=0.049). Mean age, body mass index, and transplant duration were comparable between the two groups. Neither creatinine nor GFR levels differed significantly between the two groups after the intervention(P=0.557 and P=0.387). Valacyclovir can effectively reduce the serum viral load in BKV-infected kidney transplant recipients. This reduction, however, is not accompanied by an improvement in renal function or prevention of rejection.

Energy demanding RNA and protein metabolism drive dysfunctionality of HIV-specific T cell changes during chronic HIV infection.

Antiretroviral treatment of HIV infected individuals cannot eliminate the HIV reservoir and immune control of HIV is rarely seen upon treatment interruption. In long-term non-progressors (LTNP), an effective CD8 T cell response is thought to contribute to be immune control of HIV. Here we studied the transcriptional profile of virus specific CD8 T cells during the asymptomatic phase of disease, to gain molecular insights in CD8 T cell functionality in HIV progressors and different groups of LTNP: HLA-B*57 LTNP, non-HLA-B*57 LTNP and individuals carrying the MAVS minor genotype (rs7262903/rs7269320). Principal component analysis revealed distinct overall transcriptional profiles between the groups. The transcription profile of HIV-specific CD8 T cells of LTNP groups was associated with increased cytokine/IL-12 signaling and protein/RNA metabolism pathways, indicating an increased CD8 T cell functionality. Although the transcription profile of CMV-specific CD8 T cells differed from that of HIV-specific CD8 T cells, with mainly an upregulation of gene expression in progressors, similar affected pathways were identified. Moreover, CMV-specific CD8 T cells from progressors showed increased expression of genes related to effector functions and suggests recent antigen exposure. Our data shows that changes in cytokine signaling and the energy demanding RNA and protein metabolism are related to CD8 T cell dysfunction, which may indicate that mitochondrial dysfunction is an important driver of T cell dysfunctionality during chronic HIV infection. Indeed, improvement of mitochondrial function by IL-12 and mitoTempo treatment, enhanced in vitro IFNγ release by PBMC from PWH upon HIV gag and CMV pp65 peptide stimulation. Our study provides new insights into the molecular pathways associated with CD8 T cell mediated immune control of chronic HIV infection which is important for the design of novel treatment strategies to restore or improve the HIV-specific immune response.

NKG2C and NKG2A coexpression defines a highly functional antiviral NK population in spontaneous HIV control.

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.

Identification of antibody targets associated with lower HIV viral load and viremic control.

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.