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Much has been learnt about the role of human leukocyte antigen (HLA) alleles during natural infection of HIV-1, but far less is known about their role in people living with HIV (PLWH) on suppressive antiretroviral therapy (ART). In this study we used variable selection to identify predictors of HIV reservoir size, as measured by total HIV DNA in 192 participants in an acute HIV infection (AHI) cohort. Baseline clinical data including pre-ART CD4 T cell counts and plasma viral load (VL) were available from all participants along with longitudinal measurements after ART initiation during AHI. Time to VL suppression, time to CD4 reconstitution, and pre-ART viremia were the strongest predictors of undetectable total HIV DNA at 24 weeks after ART initiation. We next performed HLA typing in 526 participants from the same cohort and investigated associations with the three predictors of reservoir size. HLA-B*57 and B*58 both associated significantly with time to VL suppression, which was one of the predictors of the size of the HIV reservoir. These findings are significant in PLWH and have to be considered in the context of therapeutic intervention when conducting analytic treatment interruption studies as participants with these alleles could impact clinical findings given the small sizes of these studies.

Background: Harnessing CD8 + T cell responses is being explored to achieve HIV remission. Although HIV-specific CD8 + T cells become dysfunctional without treatment, antiretroviral therapy (ART) partially restores their function. However, the extent of this recovery under long-term ART is less understood., Methods: We analyzed the differentiation status and function of HIV-specific CD8 + T cells after long-term ART initiated in acute or chronic HIV infection ex vivo and upon in vitro recall., Findings: ART initiation in any stage of acute HIV infection promoted the persistence of long-lived HIV-specific CD8 + T cells with high expansion (P<0·0008) and cytotoxic capacity (P=0·02) after in vitro recall, albeit at low cell number (P=0·003). This superior expansion capacity correlated with stemness (r=0·90, P=0·006), measured by TCF-1 expression, similar to functional HIV-specific CD8 + T cells found in spontaneous controllers. Importanly, TCF-1 expression in these cells was associated with longer time to viral rebound ranging from 13 to 48 days after ART interruption (r =0·71, P=0·03). In contrast, ART initiation in chronic HIV infection led to more differentiated HIV-specific CD8 + T cells lacking stemness properties and exhibiting residual dysfunction upon recall, with reduced proliferation and cytolytic activity., Interpretation: ART initiation in acute HIV infection preserves functional HIV-specific CD8 + T cells, albeit at numbers too low to control viral rebound post-ART. HIV remission strategies may need to boost HIV-specific CD8 + T cell numbers and induce stem cell-like properties to reverse the residual dysfunction persisting on ART in people treated after acute infection prior to ART release., Funding: U.S. National Institutes of Health and U.S. Department of Defense., Competing Interests: Declaration of interests All the other authors declare that they have no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

HIV-1 disrupts the host epigenetic landscape with consequences for disease pathogenesis, viral persistence, and HIV-associated comorbidities. Here, we examined how soon after infection HIV-associated epigenetic changes may occur in blood and whether early initiation of antiretroviral therapy (ART) impacts epigenetic modifications. We profiled longitudinal genome-wide DNA methylation in monocytes and CD4+ T lymphocytes from 22 participants in the RV254/SEARCH010 acute HIV infection (AHI) cohort that diagnoses infection within weeks after estimated exposure and immediately initiates ART. We identified monocytes harbored 22,697 differentially methylated CpGs associated with AHI compared to 294 in CD4+ T lymphocytes. ART minimally restored less than 1% of these changes in monocytes and had no effect upon T cells. Monocyte DNA methylation patterns associated with viral load, CD4 count, CD4/CD8 ratio, and longitudinal clinical phenotypes. Our findings suggest HIV-1 rapidly embeds an epigenetic memory not mitigated by ART and support determining epigenetic signatures in precision HIV medicine. Trial Registration: NCT00782808 and NCT00796146., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: LCN has served as an advisory board member for Abbvie, Cytodyn and ViiV for work unrelated to this project. All other authors declare no competing interests.

Background: Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4β7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection., Methods: Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I-III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin β7 (β7negative and β7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for β7-defined subsets at acute infection and in uninfected controls., Results: In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both β7high and β7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, β7high cells were enriched in integrated and total HIV-1 DNA compared to β7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both β7negative and β7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in β7high cells was correlated with their activation., Conclusions: β7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.)

CD161 expression on CD4 + T cells is associated with a Th17 functional phenotype, as well as with an innate capacity to respond to interleukin (IL)-12 and IL-18 without T cell receptor (TCR) stimulation. Chronic HIV-1 infection is associated with loss of the CD161 + CD4 T cell population, and non-human primate studies suggest that their depletion is associated with disease progression. However, the dynamics of the CD161 + CD4 + T cell population during acute HIV-1 infection remains unknown. In this study, we characterize peripheral blood CD161 + CD4 + T cells in detail, and examine how they are affected during the earliest stages of HIV-1 infection. Unbiased surface proteome screening and principal component analysis indicated that CD161 + CD4 + T cells are relatively phenotypically homogeneous between donors, and are intermediates between conventional CD4 T cells and innate-like T cells. In acute untreated HIV-1 infection, the circulating CD161 + CD4 + T cell population decreased in frequency, as did absolute cell counts starting from peak viral load, with elevated levels of activation and exhaustion markers expressed throughout acute HIV-1 infection. The capacity of these cells to respond to stimulation with IL-12 and IL-18 was also reduced. Early initiation of anti-retroviral treatment (ART) during acute HIV-1 infection restored the functionality of peripheral blood CD161 + CD4 + T cells, but not their frequency. In contrast, early ART initiation prevented the decline of colonic CD161 + CD4 + T cells that otherwise started during acute infection. Furthermore, loss of peripheral and colonic CD161 + CD4 + T cells in untreated infection was associated with levels of viral load. These results suggest that acute HIV-1 infection has profound effects on the CD161 + CD4 + T cell population that could not be completely prevented by the initiation of ART.

Background: HIV-1-specific broadly neutralising antibodies such as VRC01 could promote HIV remission by halting viral replication and clearing infected cells. We investigated whether VRC01 could promote sustained viral control off antiretroviral therapy (ART) in adults who initiated ART during acute HIV infection., Methods: We did a randomised, double-blind, placebo-controlled trial at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Eligible participants were aged 20-50 years, had initiated ART during acute infection (ie, Fiebig stages I-III), had been taking ART for more than 24 months, had fewer than 50 HIV-1 RNA copies per mL on three consecutive measurements, had more than 400 CD4 cells per μL, had fewer than ten copies of integrated HIV-1 DNA per 10 6 peripheral blood mononuclear cells, and were in generally good health. Eligible participants were randomly assigned (3:1) based on computer-generated lists with a blocking factor of 4 to receive VRC01 (40 mg/kg) or placebo (saline) intravenously every 3 weeks for up to 24 weeks during analytic interruption of ART, followed by continued observation off all therapies. Randomisation was stratified by Fiebig stage (I vs II vs III) at HIV diagnosis. Participants were monitored closely and resumed ART if 1000 or more HIV-1 RNA copies were detected per mL of plasma. The primary outcomes were the frequency of serious adverse events and the proportion of participants with fewer than 50 HIV-1 RNA copies per mL 24 weeks after treatment interruption. Efficacy analyses included all participants who received at least one full dose of study product, and safety analyses included all participants exposed to any study product. The trial was registered with ClinicalTrials.gov, number NCT02664415. This trial is completed., Findings: Between Aug 8, 2016, and Jan 9, 2017, 19 men were randomly assigned, 14 to the VRC01 group and five to the placebo group. One participant in the VRC01 group received a partial infusion without undergoing treatment interruption. The other 18 participants all received at least one full study infusion and underwent ART interruption. No serious adverse events were reported in either group. Only one participant in the VRC01 group achieved the primary efficacy endpoint of viral suppression 24 weeks after ART interruption. The other 17 restarted ART because of a confirmed recording of 1000 or more HIV-1 RNA copies per mL before 24 weeks., Interpretation: VRC01 monotherapy in individuals who initiated ART during acute HIV infection was well tolerated but did not significantly increase the number of participants with viral suppression 24 weeks after ART interruption. Further development of VRC01 and other immunotherapies for HIV will probably occur as part of combination regimens that include several treatments directed against unique therapeutic targets., Funding: US Department of the Army, US National Institutes of Health, and the Thai Red Cross AIDS Research Centre., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: Thailand plays a substantial role in global HIV-1 transmission of CRF01&#95;AE. Worldwide, men who have sex with men (MSM) are at elevated risk for HIV-1 infection. Hence, understanding HIV-1 diversity in a primarily Thai MSM cohort with acute infection, and its connections to the broader HIV-1 transmission network in Asia is crucial for research and development of HIV-1 vaccines, treatment and cure., Methods: Subtypes and diversity of infecting viruses from individuals sampled from 2009 to 2015 within the RV254/SEARCH 010 cohort were assessed by multiregion hybridization assay (MHAbce), multiregion subtype-specific PCR assay (MSSPbce) and full-length single-genome sequencing (SGS). Phylogenetic analysis was performed by maximum likelihood. Pairwise genetic distances of envelope gp160 sequences obtained from the cohort and from Asia (Los Alamos National Laboratory HIV Database) were calculated to identify potential transmission networks., Results: MHAbce/MSSPbce results identified 81.6% CRF01&#95;AE infecting strains in RV254. CRF01&#95;AE/B recombinants and subtype B were found at 7.3% and 2.8% respectively. Western subtype B strains outnumbered Thai B' strains. Phylogenetic analysis revealed one C, one CRF01&#95;AE/CRF02&#95;AG recombinant and one CRF01&#95;AE/B/C recombinant. Asian network analysis identified one hundred and twenty-three clusters, including five clusters of RV254 participants. None of the RV254 sequences clustered with non-RV254 sequences. The largest international cluster involved 15 CRF01&#95;AE strains from China and Vietnam. The remaining clusters were mostly intracountry connections, of which 31.7% included Thai nodes and 43.1% included Chinese nodes., Conclusion: While the majority of strains in Thailand are CRF01&#95;AE and subtype B, emergence of unique recombinant forms (URFs) are found in a moderate fraction of new HIV-1 infections. Approaches to vaccine design and immunotherapeutics will need to monitor and consider the expanding proportion of recombinants and the increasing genetic diversity in the region. Identified HIV-1 transmission networks indicate ongoing spread of HIV-1 among MSM. As HIV-1 epidemics continue to expand in other Asian countries, transmission network analyses can inform strategies for prevention, intervention, treatment and cure., (© 2018 Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Antiretroviral therapy during the earliest stage of acute HIV infection (Fiebig I) might minimize establishment of a latent HIV reservoir and thereby facilitate viremic control after analytical treatment interruption. We show that 8 participants, who initiated treatment during Fiebig I and were treated for a median of 2.8 years, all experienced rapid viral load rebound following analytical treatment interruption, indicating that additional strategies are required to control or eradicate HIV.

Background: Third- and fourth-generation immunoassays (IAs) are widely used in the diagnosis of human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) during acute HIV infection (AHI) may impact HIV-specific antibodies, with failure to develop antibody or seroreversion. We report on the ability of diagnostic tests to detect HIV-specific antibodies in Thai participants initiating ART during AHI., Methods: Participants with detectable plasma HIV RNA but nonreactive HIV-specific immunoglobulin G, enrolled in an AHI study, were offered immediate initiation of ART. Participants were tested at initiation and at 12 and 24 weeks following treatment using standard second-, third-, and fourth-generation IAs and Western blot (WB)., Results: Participants (N = 234) initiating ART at a median of 19 days (range, 1-62 days) from HIV exposure demonstrated different frequencies of reactivity prior to and following 24 weeks of ART depending on the IA. Third-generation IA nonreactivity prior to ART was 48%, which decreased to 4% following ART (P < .001). Fourth-generation IA nonreactivity was 18% prior to ART and 17% following ART (P = .720). Negative WB results were observed in 89% and 12% of participants prior to and following 24 weeks of ART, respectively (P < .001). Seroreversion to nonreactivity during ART was observed to at least one of the tests in 20% of participants, with fourth-generation IA demonstrating the highest frequency (11%) of seroreversion., Conclusions: HIV-specific antibodies may fail to develop and, when detected, may decline when ART is initiated during AHI. Although fourth-generation IA was the most sensitive at detecting AHI prior to ART, third-generation IA was the most sensitive during treatment., Clinical Trials Registration: NCT00796146 and NCT00796263., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

Background: Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy., Methods and Findings: We prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals. Thirty Thais were enrolled (8 Fiebig I, 5 Fiebig II, 15 Fiebig III, 2 Fiebig IV) of whom 15 completed 24 weeks of megaHAART (tenofovir/emtricitabine/efavirenz/raltegravir/maraviroc). Sigmoid biopsies were completed in 24/30 at baseline and 13/15 at week 24. At baseline, the median age was 29 years and 83% were MSM. Most were symptomatic (87%), and were infected with R5-tropic (77%) CRF01&#95;AE (70%). Median CD4 was 406 cells/mm(3). HIV RNA was 5.5 log(10) copies/ml. Median total blood HIV DNA was higher in Fiebig III (550 copy/10(6) PBMC) vs. Fiebig I (8 copy/10(6) PBMC) (p = 0.01) while the median %CD4+CCR5+ gut T cells was lower in Fiebig III (19%) vs. Fiebig I (59%) (p = 0.0008). After 24 weeks of megaHAART, HIV RNA levels of <50 copies were achieved in 14/15 in blood and 13/13 in gut. Total blood HIV DNA at week 0 predicted reservoir size at week 24 (p<0.001). Total HIV DNA declined significantly and was undetectable in 3 of 15 in blood and 3 of 7 in gut. Frequency of CD4+CCR5+ gut T cells increased from 41% at baseline to 64% at week 24 (p>0.050); subjects with less than 40% at baseline had a significant increase in CD4+CCR5+ T cells from baseline to week 24 (14% vs. 71%, p = 0.02)., Conclusions: Gut T cell depletion and HIV reservoir seeding increases with progression of AHI. MegaHAART was associated with immune restoration and reduced reservoir size. Our findings could inform research on strategies to achieve HIV drug-free remission.

Acute HIV-1 infection (AHI) results in the widespread depletion of CD4+ T cells in peripheral blood and gut mucosal tissue. However, the impact on the predominantly CD4+ immunoregulatory invariant natural killer T (iNKT) cells during AHI remains unknown. Here, iNKT cells from peripheral blood and colonic mucosa were investigated during treated and untreated AHI. iNKT cells in blood were activated and rapidly depleted in untreated AHI. At the time of peak HIV-1 viral load, these cells showed the elevated expression of cell death-associated transcripts compared to preinfection. Residual peripheral iNKT cells suffered a diminished responsiveness to in vitro stimulation early into chronic infection. Additionally, HIV-1 DNA, as well as spliced and unspliced viral RNA, were detected in iNKT cells isolated from blood, indicating the active infection of these cells in vivo. The loss of iNKT cells occurred from Fiebig stage III in the colonic mucosa, and these cells were not restored to normal levels after initiation of ART during AHI. CD4+ iNKT cells were depleted faster and more profoundly than conventional CD4+ T cells, and the preferential infection of CD4+ iNKT cells over conventional CD4+ T cells was confirmed by in vitro infection experiments. In vitro data also provided evidence of latent infection in iNKT cells. Strikingly, preinfection levels of peripheral blood CD4+ iNKT cells correlated directly with the peak HIV-1 load. These findings support a model in which iNKT cells are early targets for HIV-1 infection, driving their rapid loss from circulation and colonic mucosa. [ABSTRACT FROM AUTHOR]

Background Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4β7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection. Methods Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I–III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin β7 (β7negative and β7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for β7-defined subsets at acute infection and in uninfected controls. Results In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both β7high and β7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, β7high cells were enriched in integrated and total HIV-1 DNA compared to β7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both β7negative and β7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in β7high cells was correlated with their activation. Conclusions β7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells. [ABSTRACT FROM AUTHOR]