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.

Barriers and facilitators to pre-exposure prophylaxis (PrEP) uptake and adherence among men who have sex with men (MSM) in Thailand: a qualitative study.

Young MSM (YMSM), aged 15-24, account for nearly half of new HIV infections in Thailand. Pre-exposure prophylaxis (PrEP) is an effective prevention medicine for populations at substantial HIV risk, yet YMSM frequently have suboptimal uptake of and adherence to PrEP. We conducted 35 in-depth interviews with YMSM to explore barriers and facilitators of both PrEP initiation and adherence. Interviews also elicited the perceptions and experiences of healthcare providers (HCPs) working with YMSM at three clinics in Bangkok. Primary barriers to PrEP initiation were limited accessibility, insufficient knowledge, and efficacy concerns; HCPs identified no-to-low self-perception of HIV risk, pre-existing health problems, fears of side effects, and living in distant provinces as barriers to PrEP initiation. YMSM primarily reported PrEP information and self-perceptions of elevated HIV risk as facilitators to PrEP initiation. Additionally, forgetfulness and low HIV risk awareness were common barriers to PrEP adherence. Reminders were a prominent facilitator of PrEP adherence alongside disclosure to close relationships, the routinization of regimens, and convenient facilities. HCPs regarded counseling as the leading facilitator of PrEP adherence. By understanding the barriers/facilitators of PrEP use, the current study seeks to help develop evidence-informed PrEP intervention programs among YMSM while considering cultural sensitivity.

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.

Lived experiences with pre-exposure prophylaxis uptake and adherence among transgender women in Thailand: a qualitative study.

BACKGROUND: Transgender women (TGW) are disproportionately affected by HIV, and HIV prevalence among TGW in Thailand has been increasing. Although oral daily pre-exposure prophylaxis (PrEP) is effective for HIV prevention, PrEP uptake and persistence among TGW have been low. This study aimed to provide a deeper understanding of TGW's experiences with PrEP uptake and adherence, and to identify major barriers to PrEP use to inform intervention adaptation. METHODS: We interviewed 20 young TGW (six non-PrEP users, eight adherent, six non-adherent) and 10 health care providers from two HIV clinics in Bangkok, Thailand, in 2022. We focused on understanding challenges to PrEP use in this population using an interview guide based on a theoretical model of behaviour change and thematic content analysis. RESULTS: Thematic analysis identified major barriers to and facilitators of PrEP uptake and adherence. Barriers to PrEP initiation included low self-perceived HIV risk, concern about potential side-effects, patient burdens such as frequent HIV testing for prescription refills and social stigma against PrEP. Barriers to adherence included side-effects, inconvenient access to health services (especially during COVID-19 lockdowns), forgetfulness resulting from busy schedules and low self-perceived HIV risk. TGW also reported health care providers' stigma against PrEP users deterred them from seeking further PrEP services. TGW identified major facilitators of PrEP initiation, including awareness about the benefits of PrEP, concern about risks of HIV and supportive social networks of PrEP users. As to PrEP regimens, most TGW participants reported a clear preference for long-lasting, injectable PrEP over daily oral PrEP. TGW and health care providers largely agreed on barriers and facilitators of PrEP use, but they differed in perceptions of HIV risk. CONCLUSIONS: The results highlighted challenges and opportunities to improve the delivery of PrEP, as well as other sexually transmissable infection and mental health services, especially among TGW. Thus, there is an urgent need for developing effective intervention programs that could raise PrEP awareness and knowledge, reduce PrEP stigma, and improve PrEP delivery systems among TGW in Thailand.

Assessing the acceptability of implementing a Screening, Brief Intervention and Referral to Treatment for alcohol use among transgender women in Bangkok, Thailand: A mixed-method pre-implementation study using the Consolidated Framework for Implementation Research.

BACKGROUND AND AIMS: Health inequities related to alcohol use exist for transgender individuals. While the Thailand Ministry of Public Health recently published a clinical guideline to implement a Screening, Brief Intervention and Referral to Treatment (SBIRT) in primary care, there has been no study regarding transgender women's (TGW) alcohol use and the acceptability of implementing SBIRT in a Thai context, a gap this study aimed to fill. DESIGN: A mixed-method approach was used. In the first phase, TGW service users and health-care providers (HCPs) completed a survey on the acceptability of prospective implementation of SBIRT. TGW service users completed the Alcohol Use Disorder Identification Test-Consumption (AUDIT-C). In the second phase, TGW service users, HCPs, clinic administrators and national-level alcohol, HIV and transgender health policymakers participated in in-depth qualitative interviews. SETTING: The Tangerine Clinic, a transgender-led sexual health clinic in Bangkok, Thailand. PARTICIPANTS: In the first phase, TGW service users (n = 100) and HCP (n = 8) were surveyed. In the second phase, 22 stakeholders (n = 10 TGW service users; n = 8 HCP; n = 1 clinic administrator; n = 3 policymakers) were interviewed. MEASUREMENTS: Simple proportions were calculated for each survey item. Differences in acceptability by various demographic factors were calculated using univariate analysis. The qualitative data were coded using thematic analysis and a deductive approach. The results were mapped to the Consolidated Framework for Implementation Research domains and constructs. The quantitative and qualitative results were triangulated to expand understanding. FINDINGS: Fifty per cent of the TGW participants exhibited problematic drinking levels (AUDIT-C ≥ 4). Implementing SBIRT was highly acceptable, as more than 95% of participants reported agreeing or completely agreeing to receive SBIRT for alcohol use. Barriers, such as complexity, time constraint and lack of knowledge and skills, were anticipated. Adaptability, such as tailoring the content of brief intervention to suit TGW health needs and SBIRT to fit with existing clinic procedures, might facilitate successful implementation. CONCLUSION: Screening, Brief Intervention and Referral to Treatment (SBIRT) for alcohol use has the potential to be successfully implemented in transgender-led sexual health clinic settings, with some adaptations to overcome anticipated barriers.

Optimising HIV pre-exposure prophylaxis and testing strategies in men who have sex with men in Australia, Thailand, and China: a modelling study and cost-effectiveness analysis.

BACKGROUND: Men who have sex with men (MSM) in the Asia-Pacific region have a disproportionately high burden of HIV infection compared with the general population. Although pre-exposure prophylaxis (PrEP) for HIV is highly effective at preventing new HIV infections, the cost-effectiveness of PrEP for MSM in different countries in the Asia-Pacific region with varying PrEP coverage and HIV testing frequencies remains unstudied. We aimed to analyse the economic and health benefits of long-acting injectable cabotegravir (CAB-LA) compared with oral PrEP in high-income countries and low-income and middle-income countries within the Asia-Pacific region. METHODS: We developed a decision-analytic Markov model to evaluate the population impact and cost-effectiveness of PrEP scale-up among MSM in Australia, Thailand, and China. We assumed a static cohort of 100 000 MSM aged 18 years or older who were at risk of HIV infection, with a monthly cycle length over a 40-year time period. We evaluated hypothetical scenarios with universal PrEP coverage of 80% among 100 000 suitable MSM in each country. We modelled oral PrEP and CAB-LA for MSM with diverse HIV testing frequency strategies. We adopted the health-care system's perspective with a 3% annual discount rate. We calculated the incremental cost-effectiveness ratio (ICER), measured as additional cost per quality-adjusted life-year (QALY) gained, to compare different strategies with the status quo in each country. All costs were reported in 2021 US$. We also performed one-way, two-way, and probabilistic sensitivity analyses to assess the robustness of our findings. FINDINGS: Compared with the status quo in each country, expanding oral PrEP to 80% of suitable MSM would avert 8·1% of new HIV infections in Australia, 14·5% in Thailand, and 26·4% in China in a 40-year period. Expanding oral PrEP use with 6-monthly HIV testing for both PrEP and non-PrEP users was cost-saving for Australia. Similarly, expanding oral PrEP use remained the most cost-effective strategy in both Thailand and China, but optimal testing frequency varied, with annual testing in Thailand (ICER $4707 per QALY gained) and 3-monthly testing in China (ICER $16 926 per QALY gained) for both PrEP and non-PrEP users. We also found that replacing oral PrEP with CAB-LA for MSM could avert more new HIV infections (12·8% in Australia, 27·6% in Thailand, and 32·8% in China), but implementing CAB-LA was not cost-effective due to its high cost. The cost of CAB-LA would need to be reduced by 50-90% and be used as a complementary strategy to oral PrEP to be cost-effective in these countries. INTERPRETATION: Expanding oral PrEP use for MSM, with country-specific testing frequency, is cost-effective in Australia, Thailand, and China. Due to the high cost, CAB-LA is currently not affordable as a single-use strategy but might be offered as an additional option to oral PrEP. FUNDING: Ministry of Science and Technology of the People's Republic of China, the Australian National Health and Medical Research Council, National Key Research and Development Program of China, and National Natural Science Foundation of China.

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.

The effects of bivalent human papillomavirus (HPV) vaccination on high-risk anogenital HPV infection among sexually active female adolescents with and without perinatally acquired HIV.

BACKGROUND: Females with perinatal HIV (PHIV) infection are at elevated risk for anogenital high-risk human papillomavirus (HR-HPV) infection. Limited data are available around the effect of the HPV vaccination after initiation of sexual activity among PHIV youth. This study aims to assess the impact of a bivalent HPV vaccination on the persistence of anogenital HR-HPV among sexually active female PHIV youth and matched HIV-negative controls aged 12-24years in Thailand and Vietnam. METHODS: During a 3-year study, prevalent, incident, and persistent HR-HPV infection were assessed at annual visits. A subset of participants received a bivalent HPV vaccine. Samples were taken for HPV testing from the vagina, cervix, and anus. HR-HPV persistence was defined as the detection of the same genotype(s) at any anogenital compartment over≥two consecutive visits. RESULTS: Of the 93 PHIV and 99 HIV-negative female youth enrolled in this study, 25 (27%) PHIV and 22 (22%) HIV-negative youth received a HPV vaccine. Persistent infection with any HR-HPV type was significantly lower among PHIV youth who received the vaccine compared to those who did not (33%vs 61%, P =0.02); a difference was not observed among HIV-negative youth (35%vs 50%, P =0.82). PHIV infection (adjusted prevalence ratio [aPR] 2.31, 95% CI 1.45-3.67) and not receiving a HPV vaccine (aPR, 1.19, 95%CI 1.06-1.33) were associated with persistent anogenital HR-HPV infection. CONCLUSIONS: Bivalent HPV vaccination after initiation of sexual activity was associated with reduced persistence of anogenital HR-HPV infection in Southeast Asian PHIV female youth, which may be related to vaccine cross-protection. Primary and catch-up HPV vaccinations should be prioritised for children and youth with HIV.

CD4 dim CD8 bright T cells are inversely associated with neuro-inflammatory markers among people with HIV.

OBJECTIVE: HIV-associated neuroinflammation persists in the brain despite suppressive combination antiretroviral therapy (cART). We evaluated associations between a subset of CD8 + T cells, termed CD4 dim CD8 bright T cells, and soluble markers of immune activation and/or neuroinflammation in the cerebrospinal fluid (CSF) and plasma of people with HIV (PWH). DESIGN: Fifteen cART-naive PWH were enrolled and underwent blood draw, lumbar puncture for CSF collection, and neuropsychological tests at week 0 (pre-cART) and 24 weeks after cART initiation. METHODS: CSF and peripheral blood T cells were evaluated with flow cytometry and soluble markers of immune activation were measured by multiplex and singleplex assays. Spearman bootstrap correlation coefficients with 10 000 resamples were computed and reported with corresponding 95% confidence intervals (CIs) for each marker of interest and T-cell type. RESULTS: The frequency of CSF CD4 dim CD8 bright T cells at week 0 was inversely related with CSF neopterin. In contrast, at week 24, CSF CD4 - CD8 + T cells were positively correlated with CSF s100ß, a marker of brain injury. In the blood, at week 0, CD4 dim CD8 bright T cells were inversely correlated with MCP-1, IP-10, IL-8, IL-6, G-CSF, and APRIL and positively correlated with plasma RANTES and MMP1. At week 0, the frequency of blood CD4 - CD8 + were positively correlated with CRP and BAFF. CONCLUSION: CD4 dim CD8 bright T cells are associated with some anti-inflammatory properties, whereas CD4 - CD8 + T cells may contribute to inflammation and injury. Assessing the contrast between these two cell populations in neuroHIV may inform targeted therapeutic intervention to reduce neuroinflammation and associated neurocognitive impairment.

Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study.

BACKGROUND: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. METHODS: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. FINDINGS: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. INTERPRETATIONS: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. FUNDING: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.

Pooled Pharyngeal, Rectal, and Urine Specimens for the Point-of-Care Detection of Chlamydia trachomatis and Neisseria gonorrhoeae by Lay Providers in Key Population-Led Health Services in Thailand.

Routine testing for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in people with heightened risk is lacking in Thailand. This study aimed to assess the performance of the Cepheid Xpert CT/NG assay, conducted by key population (KP) lay providers, for CT and NG detection on single-site and pooled specimens from the pharynx, rectum, and urine. Between August and October 2019, 188 men who have sex with men and 11 transgender women were enrolled. Participants collected urine specimens while trained KP lay providers obtained pharyngeal and rectal swabs. Compared to single-site testing with the Abbott RealTime CT/NG assay by medical technologists, the Xpert assay missed one pharyngeal NG infection out of 199 single-site specimens, giving a 93.3% sensitivity for pharyngeal NG and one missed pharyngeal NG infection out of fifty pooled specimens, giving an 88.9% sensitivity for pharyngeal NG. There was no discrepancy between the two assays for CT detection. The Cohen's Kappa coefficient of pooled specimen testing by the Xpert was 0.93 for NG and 1 for CT when compared to single-site testing by Abbott. Implementing pooled specimen testing by KP lay providers can be a cost-saving strategy to enhance the uptake of CT/NG services for populations facing increased risk.

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.

Adapting Effective mHealth Interventions to Improve Uptake and Adherence to HIV Pre-Exposure Prophylaxis Among Thai Young Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial.

BACKGROUND: Young men who have sex with men (YMSM) are the fastest-growing HIV-positive population worldwide. Thailand has the highest adult HIV seroprevalence in Asia; over 25% of men having sex with men in Bangkok are HIV positive. Pre-exposure prophylaxis (PrEP) is an efficacious HIV prevention strategy recommended for all at-risk individuals. PrEP is highly effective when taken as prescribed, but PrEP utilization rate has been low, and adherence is often inadequate. OBJECTIVE: We propose to develop and pilot a multicomponent, technology-based intervention to promote motivation to begin PrEP ("uptake") and sustained adherence to PrEP among HIV-negative Thai YMSM. We will adapt an existing 2-session technology-delivered, motivational interviewing-based intervention to focus on PrEP use in YMSM in Thailand. The resulting intervention is called the Motivational Enhancement System for PrEP Uptake and Adherence (MES-PrEP). We will also develop motivational text messaging (MTM) to send two-way motivational messages to promote PrEP use. METHODS: The proposed study includes 3 phases. Phase 1 includes in-depth interviews with HIV-negative Thai YMSM and providers to explore barriers and facilitators of PrEP initiation and adherence, aiming to inform intervention content. Phase 2 consists of adapting and beta-testing MES-PrEP and MTM for functionality and feasibility using a youth advisory board of Thai YMSM. In Phase 3, we will conduct a pilot randomized controlled trial to evaluate the feasibility, acceptability, and preliminary efficacy of MES-PrEP and MTM to increase PrEP uptake and adherence among Thai YMSM. A total of 60 HIV-negative Thai YMSM who have not started PrEP and 60 YMSM who are on PrEP but not adherent to it will be randomized 2:1 to receive MES-PrEP and MTM (n=40) or standard PrEP counseling (n=20). The feasibility and acceptability of the intervention will be assessed through usage patterns and the System Usability Scale. The preliminary impact will be assessed by evaluating the proportion of PrEP initiation and level of adherence to PrEP. Participants will complete the assessments at baseline and at 1-, 3-, and 6-month postintervention. Biomarkers of adherence to PrEP and biomarkers of HIV and sexually transmitted infections will be collected. RESULTS: Recruitment for this study began in January 2022 for phase 1. Qualitative interviews were completed with 30 YMSM and 5 clinical providers in May 2022. Phase 3, the pilot feasibility and acceptability trial, began in July 2023. Upon project completion, we shall have developed a highly innovative mobile health intervention to support YMSM using PrEP, which will be ready for testing in a larger efficacy trial. CONCLUSIONS: This study addresses a critical problem (ie, high HIV incidence and low PrEP use) among Thai YMSM. We are developing 2 potentially synergistic technology-based, theory-driven interventions aimed at maximizing PrEP use. The proposed project has the potential to make significant contributions to advancing HIV prevention research and implementation science. TRIAL REGISTRATION: ClinicalTrials.gov NCT05243030; https://clinicaltrials.gov/ct2/show/NCT05243030. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46435.

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.

Single-cell transcriptomics identifies prothymosin α restriction of HIV-1 in vivo.

Host restriction factors play key roles in innate antiviral defense, but it remains poorly understood which of them restricts HIV-1 in vivo. Here, we used single-cell transcriptomic analysis to identify host factors associated with HIV-1 control during acute infection by correlating host gene expression with viral RNA abundance within individual cells. Wide sequencing of cells from one participant with the highest plasma viral load revealed that intracellular viral RNA transcription correlates inversely with expression of the gene PTMA, which encodes prothymosin α. This association was genome-wide significant (Padjusted < 0.05) and was validated in 28 additional participants from Thailand and the Americas with HIV-1 CRF01_AE and subtype B infections, respectively. Overexpression of prothymosin α in vitro confirmed that this cellular factor inhibits HIV-1 transcription and infectious virus production. Our results identify prothymosin α as a host factor that restricts HIV-1 infection in vivo, which has implications for viral transmission and cure strategies.

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.

The importance of the "how": the case for differentiated service delivery of long-acting and extended delivery regimens for HIV prevention and treatment.

INTRODUCTION: Long-acting and extended delivery (LAED) regimens for HIV treatment and prevention offer unique benefits to expand uptake, effective use and adherence. To date, research has focused on basic and clinical science around the safety and efficacy of these products. This commentary outlines opportunities in HIV prevention and treatment programmes, both for the health system and clients, that could be addressed through the inclusion of LAED regimens and the vital role of differentiated service delivery (DSD) in ensuring efficient and equitable access. DISCUSSION: The realities and challenges within HIV treatment and prevention programmes are different. Globally, more than 28 million people are accessing HIV treatment-the vast majority on a daily fixed-dose combination oral pill that is largely available, affordable and well-tolerated. Many people collect extended refills outside of health facilities with clinical consultations once or twice a year. Conversely, uptake of daily oral pre-exposure prophylaxis (PrEP) has consistently missed global targets due to limited access with high individual cost and lack of choice contributing to substantial unmet PrEP need. Recent trends in demedicalization, simplification, additional method options and DSD for PrEP have led to accelerated uptake as its availability has become more aligned with user preferences. How people currently receive HIV treatment and prevention services and their barriers to adherence must be considered for the introduction of LAED regimens to achieve the expected improvements in access and outcomes. Important considerations include the building blocks of DSD: who (provider), where (location), when (frequency) and what (package of services). Ideally, all LAED regimens will leverage DSD models that emphasize access at the community level and self-management. For treatment, LAED regimens may address challenges with adherence but their delivery should provide clear advantages over existing oral products to be scaled. For prevention, LAED regimens expand a potential PrEP user's choice of methods, but like other methods, need to be delivered in a manner that can facilitate frequent re-initiation. CONCLUSIONS: To ensure that innovative LAED HIV treatment and prevention products reach those who most stand to benefit, service delivery and client considerations during development, trial and early implementation are critical.

The Essential Need for Trust When Transmission Risk Cannot Be Eliminated in HIV-Remission Trials.

Analytic treatment interruption (ATI) is scientifically necessary in HIV-remission ("cure") studies to test the effects of new interventions. However, stopping antiretroviral treatment poses risks to research participants and their sexual partners. Ethical debate about whether and how to conduct such studies has largely centered on designing risk-mitigation strategies and identifying the responsibilities of research stakeholders. In this paper, we argue that because the possibility of HIV transmission from research participants to partners during ATI cannot practicably be eliminated-that is, it is ineliminable-the successful conduct of such trials ultimately depends on relationships of trust and trustworthiness. We describe our experiences with conducting and studying HIV-remission trials with ATI in Thailand to examine the strengths, complexities, and limitations of the risk-mitigation and responsibility approaches and to explore ways in which the building of trust-and trustworthiness-may help enhance the scientific, practical, and ethical dimensions of these trials.