Mosaic vaccine-induced antibody-dependent cellular phagocytosis associated with delayed HIV-1 viral load rebound post treatment interruption.

A heterologous Ad26/MVA vaccine was given prior to an analytic treatment interruption (ATI) in people living with HIV-1 (mainly CRF01_AE) who initiated antiretroviral treatment (ART) during acute HIV-1. We investigate the impact of Ad26/MVA vaccination on antibody (Ab)-mediated immune responses and their effect on time to viral rebound. The vaccine mainly triggers vaccine-matched binding Abs while, upon viral rebound post ATI, infection-specific CRF01_AE binding Abs increase in all participants. Binding Abs are not associated with time to viral rebound. The Ad26/MVA mosaic vaccine profile consists of correlated non-CRF01_AE binding Ab and Fc effector features, with strong Ab-dependent cellular phagocytosis (ADCP) responses. CRF01_AE-specific ADCP responses (measured either prior to or post ATI) are significantly higher in individuals with delayed viral rebound. Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption.

Neuropsychiatric and Laboratory Outcomes of Hepatitis C Treatment in an Early-Treated HIV Cohort in Thailand.

Background: Hepatitis C virus (HCV) coinfection may further compromise immunological and cognitive function in people with HIV (PWH). This study compared laboratory and neuropsychiatric measures across the periods of HCV seroconversion and direct-acting antiviral (DAA) therapy with sustained virologic response (SVR) among PWH who initiated antiretroviral therapy (ART) during acute HIV infection (AHI) and acquired HCV after 24 weeks of ART. Methods: Participants from the RV254 AHI cohort underwent paired laboratory and neuropsychiatric assessments during regular follow-up. The former included measurements of CD4 + and CD8 + T-cell counts, HIV RNA, liver enzymes, and lipid profiles. The latter included the Patient Health Questionnaire-9 (PHQ-9), Distress Thermometer (DT), and a 4-test cognitive battery that evaluated psychomotor speed, executive function, fine motor speed and dexterity. The raw scores in the battery were standardized and averaged to create an overall performance (NPZ-4) score. Parameters of HCV-coinfected participants were compared across HCV seroconversion and DAA treatment groups. Results: Between 2009 and 2022, 79 of 703 RV254 participants acquired HCV after ≥ 24 weeks of ART; 53 received DAA, and 50 (94%) achieved SVR. All participants were Thai males (median age: 30 years); 34 (68%) denied past intravenous drug use, and 41 (82%) had a history of other sexually transmitted infections during follow-up. Following SVR, aspartate transferase (AST) and alanine transaminase (ALT) decreased (p < 0.001), while total cholesterol, low-density lipoprotein, and triglycerides increased (p < 0.01). The median CD4+/CD8 + ratio increased from 0.91 to 0.97 (p = 0.012). NPZ-4 improved from 0.75 to 0.91 (p = 0.004). The median DT score increased from 1.7 to 2.7 (p = 0.045), but the PHQ-9 score remained unchanged. Conclusion: HCV coinfection is common in this group of high-risk PWH, highlighting the need for regular screening, early diagnosis, and treatment. There was a modest improvement in the CD4+/CD8 + T-cell ratio and cognitive performance after DAA therapy in patients who achieved SVR. Future studies should examine potential neuropsychiatric impacts during early HCV infection as well as the longer-term neuropsychiatric outcomes after DAA treatment with SVR.

Adaptive NK Cells Rapidly Expand during Acute HIV Infection and Persist Despite Early Initiation of Antiretroviral Therapy.

HIV is associated with NK cell dysfunction and expansion of adaptive-like NK cells that persist despite antiretroviral therapy (ART). We investigated the timing of NK cell perturbations during acute HIV infection and the impact of early ART initiation. PBMCs and plasma were obtained from people with HIV (PWH; all men who have sex with men; median age, 26.0 y) diagnosed during Fiebig stages I, II, III, or IV/V. Participants initiated ART a median of 3 d after diagnosis, and immunophenotyping was performed at diagnosis and longitudinally after ART. Anti-CMV Abs were assessed by ELISA. Samples from matched HIV-uninfected males were also analyzed. Proportions of adaptive NK cells (A-NKs; defined as Fcε-Receptor-1γ-) were expanded at HIV diagnosis at all Fiebig stages (pooled median 66% versus 25% for controls; p < 0.001) and were not altered by early ART initiation. Abs to CMV immediate early protein were elevated in PWH diagnosed in Fiebig stages III and IV/V (p < 0.03 for both). Proportions of A-NKs defined as either Fcε-Receptor-1γ- or NKG2C+/CD57+ were significantly associated with HIV DNA levels at diagnosis (p = 0.046 and 0.029, respectively) and trended toward an association after 48 wk of ART. Proportions of activated HLA-DR+/CD38+ NK cells remained elevated in PWH despite early ART initiation. NK cell activation and A-NK expansion occur very early after HIV transmission, before T cell activation, and are not altered by ART initiation during acute infection. A-NKs may contribute to HIV control and thus be useful for HIV cure.

Cerebrospinal fluid pleocytosis is associated with HIV-1 neuroinvasion during acute infection.

OBJECTIVE: HIV-1 invades the brain within days post-transmission. This study quantitated cerebrospinal fluid (CSF) white blood cell count (WBC) and investigated whether it associated with plasma and CSF HIV-1 RNA during untreated acute HIV infection (AHI). DESIGN: Seventy participants underwent lumbar puncture during Fiebig stages I-V AHI. METHOD: WBC and HIV-1 RNA with a lower limit of quantification (LLQ) of 80 copies/ml were measured in CSF. RESULTS: Sixty-nine (99%) participants were men, with a median age of 26. Their blood CD4 + and CD8 + T-cell counts were 335 [interquartile range (IQR) 247-553) and 540 (IQR 357-802) cells/µl, respectively. Forty-five (64%) were in Fiebig stages III-V whereas 25 (36%) were in Feibig stages I-II. Fifty-two (74%) experienced acute retroviral syndrome. Median plasma and CSF HIV-1 RNA were 6.10 (IQR 5.15-6.78) and 3.15 (IQR 1.90-4.11) log 10 copies/ml, respectively. Sixteen (23%) CSF samples had HIV-1 RNA below LLQ. Median CSF WBC was 2.5 (IQR 1-8) cells/µl. CSF pleocytosis (WBC >5) was observed in 33% and was only present in CSF samples with detectable HIV-1 RNA. The frequencies of CSF pleocytosis during Fiebig stages III-V and among CSF samples of higher viral load (>1000 copies/ml) were 42 and 45%, respectively. Pleocytosis independently associated with CSF HIV-1 RNA in multivariate analysis [adjusted coefficient: 0.79, 95% confidence interval (CI) 0.41-1.14), P  < 0.001] and a lower plasma to CSF HIV-1 RNA ratio ( P  < 0.001). CONCLUSION: CSF pleocytosis was present in one-third of participants with AHI. It associated with higher CSF HIV-1 RNA and a lower plasma to CSF HIV-1 RNA ratio, suggesting a potential association with HIV-1 neuroinvasion.

An active HIV reservoir during ART is associated with maintenance of HIV-specific CD8+ T cell magnitude and short-lived differentiation status.

Before initiation of antiretroviral therapy (ART), HIV-specific CD8+ T cells are dysfunctional and short lived. To better understand the relationship between the HIV reservoir in CD4+ T cells and the magnitude and differentiation status of HIV-specific CD8+ T cells, we investigated these cells from acute and chronic HIV-infected individuals after 2 years of ART. Although both the HIV reservoir and the CD8+ T cell responses declined significantly after 2 years of ART, sustained HIV-specific CD8+ T cell responses correlated with a greater reduction of integrated HIV provirus. However, the magnitude of CD8+ T cells specific for HIV Gag, Pol, Nef, and Vif proteins positively associated with the active reservoir size during ART, measured as cell-associated RNA. Importantly, high HIV DNA levels strongly associate with maintenance of short-lived HIV-specific CD8+ T cells, regardless of ART initiation time. Our data suggest that the active reservoir maintains HIV-specific CD8+ T cell magnitude but prevents their differentiation into functional cells.

Initial productive and latent HIV infections originate in vivo by infection of resting T cells.

Productively infected cells are generally thought to arise from HIV infection of activated CD4+ T cells, and these infected activated cells are thought to be a recurring source of latently infected cells when a portion of the population transitions to a resting state. We discovered and report here that productively and latently infected cells can instead originate from direct infection of resting CD4+ T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting CD4+ T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting CD4+ T cells in which expression of pTEFb enabled productive infection, and we documented persistence of HIV-producing resting T cells during antiretroviral therapy (ART). Thus, we provide evidence of a mechanism by which direct infection of resting T cells in lymphoid tissues to generate productively and latently infected cells creates a mechanism by which the productively infected cells can replenish both populations and maintain two sources of virus from which HIV infection can rebound, even if ART is instituted at the earliest stage of detectable infection.

Distinct mucosal and systemic immunological characteristics in transgender women potentially relating to HIV acquisition.

Transgender women (TGW) are disproportionally affected by HIV infection, with a global estimated prevalence of 19.9%, often attributed to behavioral risk factors, with less known about biological factors. We evaluated potential biological risk factors for HIV acquisition in TGW at the sites of viral entry by assessing immune parameters of the neovaginal surface and gut mucosa. The neovagina in TGW, compared with the vagina in cisgender women (CW), shows distinct cell composition and may pose a more inflammatory environment, evidenced by increased CD4+ T cell activation and higher levels of soluble markers of inflammation (C-reactive protein, soluble CD30). Increased inflammation may be driven by microbiome composition, as shown by a greater abundance of Prevotella and a higher Shannon Diversity Index. In addition, we have observed higher frequency of CD4+CCR5+ target cells and decreased DNA methylation of the CCR5 gene in the gut mucosa of TGW compared with CW and men who have sex with men, which was inversely correlated with testosterone levels. The rectal microbiome composition in TGW appears to favor a proinflammatory milieu as well as mucosal barrier disruption. Thus, it is possible that increased inflammation and higher frequencies of CCR5-expressing target cells at sites of mucosal viral entry may contribute to increased risk of HIV acquisition in TGW, with further validation in larger studies warranted.

HIV rapidly targets a diverse pool of CD4+ T cells to establish productive and latent infections.

Upon infection, HIV disseminates throughout the human body within 1-2 weeks. However, its early cellular targets remain poorly characterized. We used a single-cell approach to retrieve the phenotype and TCR sequence of infected cells in blood and lymphoid tissue from individuals at the earliest stages of HIV infection. HIV initially targeted a few proliferating memory CD4+ T cells displaying high surface expression of CCR5. The phenotype of productively infected cells differed by Fiebig stage and between blood and lymph nodes. The TCR repertoire of productively infected cells was heavily biased, with preferential infection of previously expanded and disseminated clones, but composed almost exclusively of unique clonotypes, indicating that they were the product of independent infection events. Latent genetically intact proviruses were already archived early in infection. Hence, productive infection is initially established in a pool of phenotypically and clonotypically distinct T cells, and latently infected cells are generated simultaneously.

Immunological, Cognitive, and Psychiatric Outcomes After Initiating Efavirenz- and Dolutegravir-based Antiretroviral Therapy During Acute Human Immunodeficiency Virus Infection.

BACKGROUND: Efavirenz (EFV)- and dolutegravir (DTG)-based antiretroviral therapy (ART) is the former and current recommended regimen for treatment-naive individuals with human immunodeficiency virus type 1 (HIV-1). Whether they impact the immunological and neuropsychiatric profile differentially remains unclear. METHODS: This retrospective analysis included 258 participants enrolled during acute HIV-1 infection (AHI). Participants initiated 1 of 3 ART regimens during AHI: EFV-based (n = 131), DTG-based (n = 92), or DTG intensified with maraviroc (DTG/MVC, n = 35). All regimens included 2 nucleoside reverse-transcriptase inhibitors and were maintained for 96 weeks. CD4+ and CD8+ T-cell counts, mood symptoms, and composite score on a 4-test neuropsychological battery (NPZ-4) were compared. RESULTS: At baseline, the median age was 26 years, 99% were male, and 36% were enrolled during Fiebig stage I-II. Plasma viral suppression at weeks 24 and 96 was similar between the groups. Compared with the EFV group, the DTG group showed greater increments of CD4+ (P < .001) and CD8+ (P = .015) T-cell counts but a similar increment of CD4/CD8 ratio at week 96. NPZ-4 improvement was similar between the 2 groups at week 24 but greater in the DTG group at week 96 (P = .005). Depressive mood and distress symptoms based on the Patient Health Questionnaire and distress thermometer were similar between the 2 groups at follow-up. Findings for the DTG/MVC group were comparable to those for the DTG group vs the EFV group. CONCLUSIONS: Among individuals with AHI, 96 weeks of DTG-based ART was associated with greater increments of CD4+ and CD8+ T-cell counts and improvement in cognitive performance.

HLA-B*57 and B*58 Associate with Predictors of Reservoir Size in an Acutely Treated HIV Cohort.

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.

Coronavirus Antibody Responses before COVID-19 Pandemic, Africa and Thailand.

Prior immune responses to coronaviruses might affect human SARS-CoV-2 response. We screened 2,565 serum and plasma samples collected from 2013 through early 2020, before the COVID-19 pandemic began, from 2,250 persons in 4 countries in Africa (Kenya, Nigeria, Tanzania, and Uganda) and in Thailand, including persons living with HIV-1. We detected IgG responses to SARS-CoV-2 spike (S) subunit 2 protein in 1.8% of participants. Profiling against 23 coronavirus antigens revealed that responses to S, subunit 2, or subunit 1 proteins were significantly more frequent than responses to the receptor-binding domain, S-Trimer, or nucleocapsid proteins (p<0.0001). We observed similar responses in persons with or without HIV-1. Among all coronavirus antigens tested, SARS-CoV-2, SARS-CoV-1, and Middle East respiratory syndrome coronavirus antibody responses were much higher in participants from Africa than in participants from Thailand (p<0.01). We noted less pronounced differences for endemic coronaviruses. Serosurveys could affect vaccine and monoclonal antibody distribution across global populations.

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8+ T cells.

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.

Acute HIV-1 infection viremia associate with rebound upon treatment interruption.

BACKGROUND: Analytic treatment interruption (ATI) studies evaluate strategies to potentially induce remission in people living with HIV-1 but are often limited in sample size. We combined data from four studies that tested three interventions (vorinostat/hydroxychloroquine/maraviroc before ATI, Ad26/MVA vaccination before ATI, and VRC01 antibody infusion during ATI). METHODS: The statistical validity of combining data from these participants was evaluated. Eleven variables, including HIV-1 viral load at diagnosis, Fiebig stage, and CD4+ T cell count were evaluated using pairwise correlations, statistical tests, and Cox survival models. FINDINGS: Participants had homogeneous demographic and clinical characteristics. Because an antiviral effect was seen in participants who received VRC01 infusion post-ATI, these participants were excluded from the analysis, permitting a pooled analysis of 53 participants. Time to viral rebound was significantly associated with variables measured at the beginning of infection: pre-antiretroviral therapy (ART) viral load (HR = 1.34, p = 0.022), time to viral suppression post-ART initiation (HR = 1.07, p < 0.001), and area under the viral load curve (HR = 1.34, p = 0.026). CONCLUSIONS: We show that higher viral loads in acute HIV-1 infection were associated with faster viral rebound, demonstrating that the initial stage of HIV-1 infection before ART initiation has a strong impact on viral rebound post-ATI years later. FUNDING: This work was supported by a cooperative agreement between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of the Army (W81XWH-18-2-0040). This research was funded, in part, by the US National Institute of Allergy and Infectious Diseases (AAI20052001) and the I4C Martin Delaney Collaboratory (5UM1AI126603-05).

HLA-B∗46 associates with rapid HIV disease progression in Asian cohorts and prominent differences in NK cell phenotype.

Human leukocyte antigen (HLA) alleles have been linked to HIV disease progression and attributed to differences in cytotoxic T lymphocyte (CTL) epitope representation. These findings are largely based on treatment-naive individuals of European and African ancestry. We assessed HLA associations with HIV-1 outcomes in 1,318 individuals from Thailand and found HLA-B∗46:01 (B∗46) associated with accelerated disease in three independent cohorts. B∗46 had no detectable effect on HIV-specific T cell responses, but this allele is unusual in containing an HLA-C epitope that binds inhibitory receptors on natural killer (NK) cells. Unbiased transcriptomic screens showed increased NK cell activation in people with HIV, without B∗46, and simultaneous single-cell profiling of surface proteins and transcriptomes revealed a NK cell subset primed for increased responses in the absence of B∗46. These findings support a role for NK cells in HIV pathogenesis, revealed by the unique properties of the B∗46 allele common only in Asia.

Paradoxically Greater Persistence of HIV RNA-Positive Cells in Lymphoid Tissue When ART Is Initiated in the Earliest Stage of Infection.

Starting antiretroviral therapy (ART) in Fiebig 1 acute HIV infection limits the size of viral reservoirs in lymphoid tissues, but does not impact time to virus rebound during a treatment interruption. To better understand why the reduced reservoir size did not increase the time to rebound we measured the frequency and location of HIV RNA+ cells in lymph nodes from participants in the RV254 acute infection cohort. HIV RNA+ cells were detected more frequently and in greater numbers when ART was initiated in Fiebig 1 compared to later Fiebig stages and were localized to the T-cell zone compared to the B-cell follicle with treatment in later Fiebig stages. Variability of virus production in people treated during acute infection suggests that the balance between virus-producing cells and the immune response to clear infected cells rapidly evolves during the earliest stages of infection. Clinical Trials Registration: NCT02919306.

Persistent HIV transcription and variable antiretroviral drug penetration in lymph nodes during plasma viral suppression.

OBJECTIVE: The ability of antiretroviral drugs to penetrate and suppress viral replication in tissue reservoir sites is critical for HIV remission. We evaluated antiretroviral concentrations in lymph nodes and their impact on HIV transcription. METHODS: Participants of the RV254/SEARCH010 Acute HIV Infection Cohort in Thailand were enrolled. Group 1 (n  = 6) initiated and continued antiretrovirals with two nucleoside reverse transcriptase inhibitors (NRTIs), dolutegravir (DTG) and mar- aviroc (MVC). Group 2 (n = 12) initiated antiretrovirals with two NRTIs as well as efavirenz and were switched to two NRTIs as well as DTG. Antiretroviral concentrations were measured by mass spectroscopy. HIV RNA+ and DNA+ cells were measured by in-situ hybridization. RESULTS: All participants were MSM. At lymph node biopsy, all had plasma HIV RNA less than 20 copies/ml. Group 2 had longer durations of antiretroviral and DTG use (medians of 135 and 63 weeks, respectively) compared with Group 1 (median 44 weeks for both). TFV-DP, 3TC-TP, DTG and MVC were quantifiable in all lymph node samples from participants receiving those drugs versus carbovir-triphosphate (CBV-TP) in four out of 14. Median ratios of lymph node to peripheral blood concentrations were DTG, 0.014; MVC, 6.9; CBV-TP, 0.38; 3TC-TP, 0.32; and TFV-DP, 3.78. Median inhibitory quotients [ratios of lymph node concentrations to in-vitro inhibitory levels (IC50-or-90)] were DTG, 0.8; MVC, 38.8; CBV-TP, 0.5; 3TC- TP, 4.1; and TFV-DP, 1.8. Ongoing viral transcription was detected in lymph node of all participants. Median lymph node RNA+ cells were 71 350 versus 99 750 cells/g for Groups 1 and 2, respectively (P = 0.111). CONCLUSION: MVC has enhanced lymph node penetration and thereby may contribute to more complete viral suppression in the lymph node.

Anti-HIV antibody development up to 1 year after antiretroviral therapy initiation in acute HIV infection.

Early initiation of antiretroviral therapy (ART) in acute HIV infection (AHI) is effective at limiting seeding of the HIV viral reservoir, but little is known about how the resultant decreased antigen load affects long-term Ab development after ART. We report here that Env-specific plasma antibody (Ab) levels and Ab-dependent cellular cytotoxicity (ADCC) increased during the first 24 weeks of ART and correlated with Ab levels persisting after 48 weeks of ART. Participants treated in AHI stage 1 had lower Env-specific Ab levels and ADCC activity on ART than did those treated later. Importantly, participants who initiated ART after peak viremia in AHI developed elevated cross-clade ADCC responses that were detectable 1 year after ART initiation, even though clinically undetectable viremia was reached by 24 weeks. These data suggest that there is more germinal center (GC) activity in the later stages of AHI and that Ab development continues in the absence of detectable viremia during the first year of suppressive ART. The development of therapeutic interventions that can enhance earlier development of GCs in AHI and Abs after ART initiation could provide important protection against the viral reservoir that is seeded in individuals treated early in the disease.

Preferential and persistent impact of acute HIV-1 infection on CD4+ iNKT cells in colonic mucosa.

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.

Brief Report: Prevalence Trend of Transmitted Drug Resistance in a Prospective Cohort of Thai People With Acute HIV Infection.

BACKGROUND: The greater availability of different antiretroviral therapy regimens in developing countries may influence the emergence of transmitted drug resistance (TDR). People with acute HIV infection (AHI) represent the best opportunity for real-time monitoring of TDR. This study assessed the TDR prevalence trends over time in a Thai cohort of predominantly men who have sex with men (MSM) with AHI. METHODS: At the time of RV254/SEARCH010 study (NCT00796146) enrollment and before starting ART, HIV genotyping was used to identify mutations in the reverse transcriptase and protease genes. Testing for TDR mutations was obtained by a validated in-house method with TRUGENE assay in a subset. Genotype sequences were analyzed using the Stanford University HIV Drug Resistance Database. RESULTS: Genotyping was performed for 573 participants with AHI. Their median age was 26 years (interquartile range 22-31), 97.4% were men, and 94.1% were MSM. Overall TDR prevalence was 7.0%, declining from 12.5% in 2009-2010 to 4.8% in 2017-2018. A declining resistance prevalence to nonnucleoside reverse transcriptase inhibitor emerged from 9.4% in 2009-2010 to 3.5% in 2017-2018 and to nucleoside reverse transcriptase inhibitor from 6.3% to 2.1%. Protease inhibitor resistance showed a decreased TDR level from 3.1% in 2009-2010 to 1.4% in 2017-2018. CONCLUSIONS: We report an encouraging declining trend in TDR prevalence in a Thai cohort of mainly MSM from 2009 to 2018; in 2017-2018, we observed a low TDR prevalence according to the World Health Organization definition.

Brief Report: Syphilis Incidence and Effect on Viral Load, CD4, and CD4/CD8 Ratio in a Thai Cohort of Predominantly Men Who Have Sex With Men Living With HIV.

BACKGROUND: Syphilis has been increasing in the past years, especially among men who have sex with men (MSM). The aim of the study was to assess syphilis prevalence and incidence and changes in CD4 count and viremia in the RV254 cohort of persons living with HIV who initiated antiretroviral therapy during acute HIV infection (AHI) in Bangkok, Thailand. METHODS: From 2009 to 2018, all cohort participants with AHI were tested for syphilis using a qualitative treponemal chemiluminescent microparticle immunoassay and rapid plasma reagin on enrollment, every 24-48 weeks thereafter and when clinically indicated. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with incident syphilis. RESULTS: Among 579 participants, the median age was 26 (interquartile range: 22-31) years and 564 (97.4%) were men. Syphilis prevalence at enrollment was 14.3% and incidence was 10.2 cases per 100 person-years. Participants with syphilis were more likely to be MSM (HR 3.68, 95% CI: 1.16 to 11.62), use methamphetamine (HR 2.31, 95% CI: 1.51 to 3.54), and have hepatitis C (HR 2.63, 95% CI: 1.59 to 4.34). HIV RNA >50 copies/mL occurred in 6 (3.9%) participants at incident syphilis diagnosis and in 6 (3.9%) after syphilis treatment. Median CD4 count (cells/mm3) declined from 663 before syphilis to 624 at syphilis diagnosis (P = 0.07), rising again to 660 after syphilis treatment. CONCLUSION: Syphilis was common in the RV254 cohort, inducing a marginal but significant impact on HIV RNA and a temporary decline in CD4. Syphilis screening and behavioral risk reduction counseling should be implemented for MSM with AHI in Thailand.