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Productively infected cells are generally thought to arise from HIV infection of activated [CD4.sup.+] 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.sup.+] T cell populations in lymphoid tissues in Fiebig I, the earliest stage of detectable HIV infection. We found that direct infection of resting [CD4.sup.+] T cells was correlated with the availability of susceptible target cells in lymphoid tissues largely restricted to resting [CD4.sup.+] 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., Introduction From the beginning of HIV research, HIV has been mainly propagated in vitro in tissue cultures of activated [CD4.sup.+] T cells (1), leading to the prevailing view that activated [...]

COVID-19 clinical manifestations range from asymptomatic infection to death. Whether prior immune responses to human coronaviruses affect responses to SARS-CoV-2 remains unclear. At the population level, disparities in COVID-19 outcomes [...]

IntroductionLiver disease is a common cause of non-AIDS morbidity and mortality in people living with HIV (PLHIV), but the prevalence and significance of liver function test (LFT) abnormalities in early HIV infection is unknown. This study aimed to characterize LFTs in a large cohort of participants with acute HIV infection initiating immediate antiretroviral therapy (ART) and examine the association between LFTs and biomarkers of HIV infection and inflammation.MethodsWe measured LFTs at the time of HIV diagnosis and at 4, 12, 24 and 48 weeks after ART initiation in 426 Thai individuals with acute HIV infection from 2009 to 2018. A subset of individuals had data available at 96 and 144 weeks. We excluded individuals with concomitant viral hepatitis. Alanine aminotransferase (ALT) was the primary outcome of interest; values greater than 1.25 times the upper limit of normal were considered elevated. Analyses utilized descriptive statistics, non-parametric tests and multivariate logistic regression.ResultsSixty-six of the 426 individuals (15.5%) had abnormal baseline ALT levels; the majority (43/66, 65.5%) had Grade 1 elevations. Elevated baseline ALT correlated with Fiebig stages III to V (p = 0.001) and baseline HIV RNA >6 log10 copies/mL (p = 0.012). Baseline elevations resolved by 48 weeks on ART in 59 of the 66 individuals (89%). ALT elevations at 24 and 48 weeks correlated with Fiebig stages I to II at diagnosis (p 350 cells/μL (p = 0.03) and older age (p = 0.03). Individuals initiating efavirenz-based regimens were more likely to have elevated ALT levels at 48 weeks compared with those on non-efavirenz-based regimens (p = 0.003).ConclusionsOne in six people with acute HIV infection have elevated LFTs. Clinical outcomes with ART started in acute HIV are generally good, with resolution of ALT elevations within 48 weeks on ART in most cases. These results suggest a multifactorial model for hepatic injury involving a combination of HIV-associated and ART-associated processes, which may change over time.

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/[mm.sup.3] despite plasma viral suppression. We investigated the frequency and associations of suboptima CD4 recovery after ART started during acute HIV infection (AHI). Methods: Participants who started ART in Fiebig I to V AHI with [greater than or equal to]48 weeks of continuous documented HIV-RNA< 50 copies/mL were stratified by CD4 count at latest study visit to suboptimal immune recovery (SIR; CD4 < 350 cells/[mm.sup.3]), intermediate immune recovery (IIR; 350 [less than or equal to] CD4 < 500) and complete immune recovery (CIR; CD4 [greater than or equal to] 500). Clinical and laboratory parameters were assessed at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral end-points were examined at baseline and 96 weeks. Results: Of 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60 to 420) weeks of ART initiated at median 19 days (range 1 to 62) post-exposure, 3.6% (n = 11) had SIR and 14.5% (n = 44) had IIR. Pre-ART CD4 count in SIR compared to CIR participants was 265 versus 411 cells/[mm.sup.3] (p = 0.002). Individuals with SIR or IIR had a slower CD4 rate of recovery compared to those with CIR. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Following ART, the [CD8.sup.+]T cell count (p = 0.001) and CD4/CD8 ratio (p = 0.047) were lower in SIR compared to CIR participants. Compared to the CIR group at week 96, the combined SIR and IIR groups had higher sCD14 (p = 0.008) and lower IL-6 (p = 0.04) in plasma, without differences in neuropsychological or psychiatric indices. Conclusions: Despite immediate and sustained treatment in AHI, suboptimal CD4 recovery occurs uncommonly and is associated with low pre-ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment. Keywords: ARV; Asia; men who have sex with men; LMIC; immunology; HIV care continuum Additional information may be found under the Supporting Information tab for this article., 1 | INTRODUCTION In the era of potent antiretroviral therapy (ART), ongoing HIV replication is adequately suppressed to undetectable levels in appropriately treated individuals. However, up to 30% of ART-treated [...]

Infusion of the broadly neutralizing antibody VRC01 has been evaluated in individuals chronically infected with HIV-1. Here, we studied how VRC01 infusions affected viral rebound after cessation of antiretroviral therapy (ART) in 18 acutely treated and durably suppressed individuals. Viral rebound occurred in all individuals, yet VRC01 infusions modestly delayed rebound and participants who showed a faster decay of VRC01 in serum rebounded more rapidly. Participants with strains most sensitive to VRC01 or with VRC01 epitope motifs similar to known VRC01- susceptible strains rebounded later. Upon rebound, HIV-1 sequences were indistinguishable from those sampled at diagnosis. Across the cohort, participant-derived Env showed different sensitivity to VRC01 neutralization (including 2 resistant viruses), yet neutralization sensitivity was similar at diagnosis and after rebound, indicating the lack of selection for VRC01 resistance during treatment interruption. Our results showed that viremia rebounded despite the absence of HIV-1 adaptation to VRC01 and an average VRC01 trough of 221 micro]g/mL. Although VRC01 levels were insufficient to prevent a resurgent infection, knowledge that they did not mediate Env mutations in acute-like viruses is relevant for antibody-based strategies in acute infection., Introduction Analytic treatment interruption (ATI) studies can help evaluate strategies to mediate long-term remission in HIV-1-infected persons. An ATI study tested the impact of the administration of the broadly neutralizing [...]

Plasmacytoid dendritic cells (pDCs) are robust producers of IFN[alpha] and one of the first immune cells to respond to SIV infection. To elucidate responses to early HIV-1 replication, we studied blood pDCs in 29 HIV-infected participants who initiated antiretroviral therapy during acute infection and underwent analytic treatment interruption (ATI). We observed an increased frequency of partially activated pDCs in the blood before detection of HIV RNA. Concurrent with peak pDC frequency, we detected a transient decline in the ability of pDCs to produce IFN[alpha] in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-[kappa]B. The levels of phosphorylated IRF7 and NF-[kappa]B inversely correlated with plasma IFNA2 levels, implying that pDCs were refractory to in vitro stimulation after IFN[alpha] production in vivo. After ATI, decreased expression of IFN genes in pDCs inversely correlated with the time to viral detection, suggesting that pDC IFN loss is part of an effective early immune response. These data from a limited cohort provide a critical first step in understanding the earliest immune response to HIV-1 and suggest that changes in blood pDC frequency and function can be used as an indicator of viral replication before detectable plasma viremia., Introduction Plasmacytoid dendritic cells (pDCs) are important mediators of the early innate immune response to viral infection through robust production of type I IFNs, particularly IFN[alpha] (1, 2). pDCs recognize [...]

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., Introduction Initiation of antiretroviral therapy (ART) during acute HIV infection (AHI) is associated with multiple benefits, including decreased HIV reservoir size (1-6) and preservation of a homogenous viral reservoir with [...]

Although HIV-associated dementia (HAD) occurs in less than 5 % of individuals with access to combination antiretroviral therapy, rates of milder forms of HIV-associated neurocognitive disorder (HAND) are much higher. We sought to define an optimal cut point for the International HIV Dementia Scale (IHDS) in Thailand for the identification of symptomatic HAND, defined as both HAD and mild neurocognitive disorder. We then sought to determine if adding a simple test from a larger neuropsychological battery could improve the performance characteristics for identifying symptomatic HAND. In this study, subjects comprising 75 seropositive adults in Bangkok, Thailand, completed neuropsychological tests and underwent a full neurological assessment. HAND diagnoses were determined by consensus conference using the 2007 Frascati criteria, blinded to the IHDS results. The optimal IHDS cut point was determined by receiver operating characteristic analysis with cross-validation. Individual neuropsychological tests were then evaluated and combined with the IHDS to test performance characteristics. The IHDS was poor at detecting symptomatic HAND at the optimized cut point of ≤ 10 (sensitivity, 53.3 %; specificity, 89.8 %). Trail Making Test A was most effective in improving performance characteristics when combined with the IHDS, with net sensitivity of 86 % and specificity of 79 %. In this setting, the IHDS performed poorly in identifying symptomatic HAND, but was substantially improved by the addition of Trail Making Test A, which typically requires less than 2 min to complete. This combination should be validated in a larger setting since it may address the critical need for HAND screening instruments in international settings.

Introduction: Thailand plays a substantial role in global HIV-1 transmission of CRF01_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% CRF01AE infecting strains in RV254. CRF01AE/B recombinants and sub-type 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_AE/CRF02_AG recombinant and one CRF01_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 CRF01AE 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 CRF01AE 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. Keywords: HIV-1 molecular epidemiology; Thailand; Asia transmission network; MSM; acute infection; recombinants; vaccine; intervention, Additional Supporting Information may be found online in the Supporting information tab for this article. 1 INTRODUCTION Over 30 years have passed since the first case of HIV-1 was reported [...]

BackgroundDue to superior long-term toxicity profiles, zidovudine (AZT) and tenofovir disoproxil fumarate (TDF) are preferred over stavudine (d4T) for first-line antiretroviral regimens. However, short-term d4T use could be beneficial in avoiding AZT-induced anaemia.MethodsWe randomized (1:1:1) 150 treatment-naive Thai HIV-infected adults with CD4(+) T-cell count

BackgroundLimited 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 findingsWe 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_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 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).ConclusionsGut 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.

ObjectiveSingle voxel proton magnetic resonance spectroscopy (MRS) can be used to monitor changes in brain inflammation and neuronal integrity associated with HIV infection and its treatments. We used MRS to measure brain changes during the first weeks following HIV infection and in response to antiretroviral therapy (ART).MethodsBrain metabolite levels of N-acetyl aspartate (NAA), choline (tCHO), creatine (CR), myoinositol (MI), and glutamate and glutamine (GLX) were measured in acute HIV subjects (n = 31) and compared to chronic HIV+individuals (n = 26) and HIV negative control subjects (n = 10) from Bangkok, Thailand. Metabolites were measured in frontal gray matter (FGM), frontal white matter (FWM), occipital gray matter (OGM), and basal ganglia (BG). Repeat measures were obtained in 17 acute subjects 1, 3 and 6 months following initiation of ART.ResultsAfter adjustment for age we identified elevated BG tCHO/CR in acute HIV cases at baseline (median 14 days after HIV infection) compared to control (p = 0.0014), as well as chronic subjects (p = 0.0023). A similar tCHO/CR elevation was noted in OGM; no other metabolite abnormalities were seen between acute and control subjects. Mixed longitudinal models revealed resolution of BG tCHO/CR elevation after ART (p = 0.022) with tCHO/CR similar to control subjects at 6 months.InterpretationWe detected cellular inflammation in the absence of measurable neuronal injury within the first month of HIV infection, and normalization of this inflammation following acutely administered ART. Our findings suggest that early ART may be neuroprotective in HIV infection by mitigating processes leading to CNS injury.

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. Initiation of antiretroviral therapy in the first 2 weeks of HIV infection fails to prevent resurgence of virus after stopping treatment, indicating early establishment of a resilient viral reservoir., Author(s): Donn J. Colby [sup.1] , Lydie Trautmann [sup.2] [sup.3] , Suteeraporn Pinyakorn [sup.2] [sup.3] , Louise Leyre [sup.4] , Amélie Pagliuzza [sup.4] , Eugène Kroon [sup.1] , Morgane Rolland [...]

Introduction: The extent of viral replication during acute HIV infection (AHI) influences HIV disease progression. However, information comparing viral load (VL) kinetics with and without antiretroviral therapy (ART) in AHI is limited. The knowledge gained could inform preventive strategies aimed at reducing VL during AHI and therapeutic strategies to alter the viral kinetics that may enhance the likelihood of achieving HIV remission. Methods: The analysis utilized VL data captured during the first year of HIV infection from two studies in Thailand: the RV217 study (untreated AHI, 30 participants and 412 visits) and the RV254 study (treated AHI, 235 participants and 2803 visits). Fiebig stages were I/II (HIV RNA+, HIV IgM-) and Fiebig III/IV (HIV IgM+, Western blot-/indeterminate). Data were modelled utilizing spline effects within a linear mixed model, with a random intercept and slope to allow for between-subject variability and adjustment for the differences in variability between studies. The number of knots in the quadratic spline basis functions was determined by comparing models with differing numbers of knots via the Akaike Information Criterion. Models were fit using PROC GLIMMIX in SAS v9.3. Results: At enrolment, there were 24 Fiebig I/II and 6 Fiebig III/IV individuals in the untreated group and 137 Fiebig I/II and 98 Fiebig III/IV individuals in the treated group. Overall, the median age was 27.5 years old, most were male (89%), and CRF01_AE was the most common HIV clade (76%). By day 12 (4 days after ART in RV254), the untreated group had a 2.7-fold higher predicted mean VL level compared to those treated (predicted log VL 6.19 for RV217 and 5.76 for RV254, p = 0.05). These differences increased to 135-fold by day 30 (predicted log VL 4.89 for RV217 and 2.76 for RV254) and 1148-fold by day 120 (predicted log VL 4.68 for RV217 and 1.63 for RV254) (p < 0.0001 for both) until both curves were similarly flat at about day 150 (p = 0.17 between days 150 and 160). The VL trajectories were significantly different between Fiebig I/II and Fiebig III/IV participants when comparing the two groups and within the treated group (p < 0.001 for both). Conclusions: Initiating ART in AHI dramatically changed the trajectory of VL very early in the course of infection that could have implications for reducing transmission potential and enhancing responses to future HIV remission strategies. There is an urgency of initiating ART when acute infection is identified. New and inexpensive strategies to engage and test individuals at high risk for HIV as well as immediate treatment access will be needed to improve the treatment of acute infection globally. Clinical Trial Number: NCT00796146 and NCT00796263 Keywords: HIV; viral load; acute HIV; ART; early treatment; mathematical modelling, Introduction The extent of viral replication during acute HIV infection (AHI) influences HIV disease progression. Most notably, viral set point levels in early infection predict time to clinical AIDS [1,2]. [...]

Introduction: Antiretroviral treatment (ART) reduces HIV transmission. Despite increased ART coverage, incidence remains high among men who have sex with men (MSM) in many places. Acute HIV infection (AHI) is characterized by high viral replication and increased infectiousness. We estimated the feasible reduction in transmission by targeting MSM with AHI for early ART. Methods: We recruited a cohort of 88 MSM with AHI in Bangkok, Thailand, who initiated ART immediately. A risk calculator based on viral load and reported behaviour, calibrated to Thai epidemiological data, was applied to estimate the number of onwards transmissions. This was compared with the expected number without early interventions. Results: Forty of the MSM were in 4th-generation AHI stages 1 and 2 (4thG stage 1, HIV nucleic acid testing (NAT)+/4thG immunoassay (IA)-/3rdG IA-; 4thG stage 2, NAT+/4thG IA+/3rdG IA-) while 48 tested positive on third-generation IA but had negative or indeterminate western blot (4thG stage 3). Mean plasma HIV RNA was 5.62 [log.sub.10] copies/ml. Any condomless sex in the four months preceding the study was reported by 83.7%, but decreased to 21.2% by 24 weeks on ART. After ART, 48/88 (54.6%) attained HIV RNA Conclusions: Disproportionate HIV transmission occurs during AHI. Diagnosis of AHI with early ART initiation can substantially reduce onwards transmission. Keywords: HIV; acute infection; men who have sex with men; models/projections; prevention of sexual transmission; behavioural interventions; antiretroviral therapy, Introduction Antiretroviral treatment (ART) reduces HIV viral load and HIV transmission in HIV-discordant heterosexual couples [1-6]. However, despite increased uptake of ART since 1996, HIV incidence continues to rise among [...]

: Introduction: Dolutegravir (DTG) is recommended as part of first‐line antiretroviral therapy (ART) for people living with HIV(PLHIV). We sought to determine the rate of adverse events (AEs) and discontinuations among Thais treated during acute HIV infection (AHI) and switched to DTG‐based regimens. Methods: Thai participants in the SEARCH010/RV254 cohort who initiated ART during AHI and switched to DTG for at least 48 weeks were prospectively observed and included in the analysis. Rates and characteristics of DTG‐related AEs and discontinuations were described. Results: A total of 313 Thai participants were included in the analysis. The median age was 29 years, 96% were male, 64% had a Bachelor's degree or higher and 16% had a body mass index (BMI) Conclusions: DTG was well tolerated with few discontinuations in this cohort of young men. Incident hepatitis C virus infection was a driver of liver‐related AEs leading to discontinuations. In populations at risk, regular testing for hepatitis C virus during ART is recommended to anticipate possible AEs, guide management and improve safety., Introduction Dolutegravir (DTG) is a potent second generation HIV integrase strand transfer inhibitor (INSTI) with a favourable profile of efficacy, safety and tolerability in adults and adolescents. It has a [...]

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. [ABSTRACT FROM AUTHOR]