Publications by authors named "Jintanat Ananworanich"

323 Publications

Dynamics of Human Immunodeficiency Virus-1 Genetic Diversification During Acute Infection.

Open Forum Infect Dis 2020 Oct 12;7(10):ofaa429. Epub 2020 Sep 12.

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

We analyzed human immunodeficiency virus envelope diversity in 98 acute infections. The within-host genetic diversity, divergence from transmitted/founder (T/F) strain, and the observed frequency of multiple T/F infections increased with Fiebig stage. These data identify rapid viral dynamics during acute infection with implications for clinical trials conducted in this setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958800PMC
October 2020

Viral Rebound Kinetics Correlate with Distinct HIV Antibody Features.

mBio 2021 03 9;12(2). Epub 2021 Mar 9.

Ragon Institute of MGH, MIT and Harvard, Cambridge, Massachusetts, USA

Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy (ART) is interrupted. The kinetics of viral rebound, specifically the time until plasma virus becomes detectable, differ quite substantially between individuals, and associations with virological and immunological factors have been suggested. Standard clinical measures, like CD4 T-cell counts and plasma HIV RNA levels, however, are poor predictive markers. Antibody features, including Fc functionality and Fc glycosylation have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we analyzed HIV-specific antibody quantities and qualitative differences like antibody-mediated functions, Fc gamma receptor (FcγR) binding, and IgG Fc glycosylation as well as cytokine profiles and cellular HIV DNA and RNA levels in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders (≤4 weeks versus >4 weeks) and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. Specifically, individuals with early viral rebound exhibited higher levels of total HIV-specific IgGs carrying inflammatory Fc glycans, while delayed rebounders showed an enrichment of highly functional antibodies. Overall, only four features, including enhanced antibody-mediated NK cell activation in delayed rebounders, were necessary to discriminate the groups. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future ATI studies. Plasma viremia reoccurs in most HIV-infected individuals once antiretroviral therapy is interrupted, and interindividual differences in the kinetics of viral rebound have been associated with virological and immunological factors. Antibody features, including Fc functionality and Fc glycosylation, have been identified as sensitive surrogates for disease activity in multiple diseases. Here, we systematically analyzed HIV-specific antibody quantities and qualitative differences in 23 ART-suppressed individuals prior to undergoing an analytical ART interruption (ATI). We found that antibodies with distinct functional properties and Fc glycan signatures separated individuals into early and delayed viral rebounders and tracked with levels of inflammatory cytokines and transcriptional activity of the viral reservoir. These data suggest that antibody features can be used as sensitive indicators of HIV disease activity and could be included in future HIV eradication studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.00170-21DOI Listing
March 2021

Cognitive trajectories after treatment in acute HIV infection.

AIDS 2021 05;35(6):883-888

Missouri Institute of Mental Health, University of Missouri-St. Louis, Missouri, USA.

Objective: People with HIV continue to exhibit cognitive symptoms after suppressive antiretroviral therapy (ART). It remains unclear if initiating ART during acute HIV-1 infection (AHI) uniformly improves cognitive outcomes.

Methods: Sixty-seven individuals (96% men, median age 28 years) initiated ART immediately after AHI diagnosis and maintained viral suppression for 6 years. They underwent a four-test neuropsychological battery that measured fine motor speed and dexterity, psychomotor speed, and executive functioning at baseline (pre-ART AHI), weeks 12, 24 and 96, and annually thereafter through week 288. Performances were standardized to calculate an overall (NPZ-4) score and frequencies of impaired cognitive performance (≤-1 SD on at least two tests, or ≤-2 SD on at least one test). Group-based trajectory analysis (GBTA) was applied to identify distinct neuropsychological trajectories modelled from baseline to week 288. Posthoc analyses examined HIV-1 and demographic factors that differed between trajectory subgroups.

Results: NPZ-4 scores improved from baseline to week 96 (P < 0.001) and from weeks 96 to 288 (P < 0.001), with frequencies of impaired performance of 30, 6 and 2% at the respective time-points. The amplitude of NPZ-4 improvement throughout the period was more than 0.5 SD and beyond practice effects. GBTA identified three NPZ-4 trajectory subgroups that all showed improvement over-time. The subgroup with lowest baseline performance exhibited worse depressive symptoms at baseline (P = 0.04) and the largest improvement among the three. HIV-1 indices did not differ between the subgroups.

Conclusion: Cognitive performance improved in a sustained and stable manner after initiating ART during AHI. Largest improvements were seen in participants with worst baseline cognitive performance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000002831DOI Listing
May 2021

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes.

EBioMedicine 2021 Jan 12;63:103175. Epub 2021 Jan 12.

Department of Infectious Diseases and Microbiology, University of Pittsburgh, Graduate School of Public Health, Pittsburgh, PA, United States. Electronic address:

Background: During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV).

Methods: Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome.

Findings: MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures.

Interpretation: Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection.

Funding: A full list of the funding sources is detailed in the Acknowledgment section of the manuscript.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ebiom.2020.103175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811131PMC
January 2021

Association of Immunosuppression and Viral Load With Subcortical Brain Volume in an International Sample of People Living With HIV.

JAMA Netw Open 2021 01 4;4(1):e2031190. Epub 2021 Jan 4.

Imaging Genetics Center, Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Marina del Rey.

Importance: Despite more widely accessible combination antiretroviral therapy (cART), HIV-1 infection remains a global public health challenge. Even in treated patients with chronic HIV infection, neurocognitive impairment often persists, affecting quality of life. Identifying the neuroanatomical pathways associated with infection in vivo may delineate the neuropathologic processes underlying these deficits. However, published neuroimaging findings from relatively small, heterogeneous cohorts are inconsistent, limiting the generalizability of the conclusions drawn to date.

Objective: To examine structural brain associations with the most commonly collected clinical assessments of HIV burden (CD4+ T-cell count and viral load), which are generalizable across demographically and clinically diverse HIV-infected individuals worldwide.

Design, Setting, And Participants: This cross-sectional study established the HIV Working Group within the Enhancing Neuro Imaging Genetics Through Meta Analysis (ENIGMA) consortium to pool and harmonize data from existing HIV neuroimaging studies. In total, data from 1295 HIV-positive adults were contributed from 13 studies across Africa, Asia, Australia, Europe, and North America. Regional and whole brain segmentations were extracted from data sets as contributing studies joined the consortium on a rolling basis from November 1, 2014, to December 31, 2019.

Main Outcomes And Measures: Volume estimates for 8 subcortical brain regions were extracted from T1-weighted magnetic resonance images to identify associations with blood plasma markers of current immunosuppression (CD4+ T-cell counts) or detectable plasma viral load (dVL) in HIV-positive participants. Post hoc sensitivity analyses stratified data by cART status.

Results: After quality assurance, data from 1203 HIV-positive individuals (mean [SD] age, 45.7 [11.5] years; 880 [73.2%] male; 897 [74.6%] taking cART) remained. Lower current CD4+ cell counts were associated with smaller hippocampal (mean [SE] β = 16.66 [4.72] mm3 per 100 cells/mm3; P < .001) and thalamic (mean [SE] β = 32.24 [8.96] mm3 per 100 cells/mm3; P < .001) volumes and larger ventricles (mean [SE] β = -391.50 [122.58] mm3 per 100 cells/mm3; P = .001); in participants not taking cART, however, lower current CD4+ cell counts were associated with smaller putamen volumes (mean [SE] β = 57.34 [18.78] mm3 per 100 cells/mm3; P = .003). A dVL was associated with smaller hippocampal volumes (d = -0.17; P = .005); in participants taking cART, dVL was also associated with smaller amygdala volumes (d = -0.23; P = .004).

Conclusions And Relevance: In a large-scale international population of HIV-positive individuals, volumes of structures in the limbic system were consistently associated with current plasma markers. Our findings extend beyond the classically implicated regions of the basal ganglia and may represent a generalizable brain signature of HIV infection in the cART era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamanetworkopen.2020.31190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811179PMC
January 2021

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.

J Acquir Immune Defic Syndr 2021 Feb;86(2):219-223

SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002542DOI Listing
February 2021

Novel Criteria for Diagnosing Acute and Early HIV Infection in a Multi-National Study of Early Antiretroviral Therapy Initiation.

Clin Infect Dis 2020 Dec 31. Epub 2020 Dec 31.

Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.

Background: Antiretroviral therapy (ART) initiation during acute and early HIV infection (AEHI) limits HIV reservoir formation and may facilitate post-ART control but is logistically challenging. We evaluated the performance of new AEHI diagnostic criteria from a multi-national prospective study of ART initiation during AEHI.

Methods: ACTG 5354 enrolled adults at 30 sites in the Americas, Africa, and Asia who met any one of six criteria based on combinations of results of HIV RNA, HIV antibody, Western blot or Geenius assay, and/or the signal-to-cutoff (S/CO) ratio of the ARCHITECT HIV Combo Ag/Ab CMIA or GS HIV COMBO Ag/Ab EIA. HIV infection and Fiebig stage were subsequently confirmed by centralized testing.

Results: From 2017-2019, 195 participants were enrolled with median age 27 (interquartile range 23-39) years. Thirty (15.4%) were female. ART was started by 171 (87.7%) on the day of enrollment and 24 (12.3%) the next day. AEHI was confirmed in 188 (96.4%) participants after centralized testing, four (2.0%) participants were retrospectively found to have chronic infection, and three (1.5%) found not to have HIV discontinued ART and were withdrawn. Retrospectively, a nonreactive or indeterminate HIV antibody on the Geenius assay combined with ARCHITECT S/CO ≥10 correctly identified 99 of 122 (81.2%) Fiebig II-IV AEHI cases with no false-positive results.

Conclusions: Novel AEHI criteria incorporating ARCHITECT S/CO into diagnostic algorithms facilitated rapid and efficient ART initiation without waiting for an HIV RNA result. These new criteria may facilitate AEHI diagnosis, staging, and immediate ART initiation in future research studies and clinical practice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1893DOI Listing
December 2020

HIV-related enacted stigma and increase frequency of depressive symptoms among Thai and Cambodian adolescents and young adults with perinatal HIV.

Int J STD AIDS 2021 Mar 18;32(3):246-256. Epub 2020 Dec 18.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Center, Bangkok, Thailand.

HIV-related enacted stigma and social problems may increase risk for depression and/or behavioral problems among adolescents and young adults with perinatal HIV(AYA-PHIV), yet few studies have explored stigma in AYA-PHIV residing in low-to-middle income regions, including Southeast Asia. We assessed HIV-related enacted stigma and social problems in AYA-PHIV who participated in the RESILIENCE study (clinicaltrials.gov identification: U19AI53741) in Thailand and Cambodia using specific questions during structured in-person interviews. Depression was measured by the Child Depression Inventory for children <15 years, or the Center for Epidemiologic Studies Depression Scales for youth ≥15 years); behavioral problems were measured by the Child Behavior Checklist (CBCL-caregiver report). Among 195 AYA-PHIV (median age 16.9 years), 25.6% reported a lifetime experience of enacted stigma, while 10.8% experienced social problems due to HIV infection. The frequency of depressive symptoms was nearly two-fold higher among AYA-PHIV with compared to those without HIV-related enacted stigma (34.7% vs. 16.0%, p = 0.005). Caregiver-reported behavioral problems were detected in 14.6% of all AYA-PHIV, with no differences between those with and without HIV-related enacted stigma. Low household income and caregiver mental health problems were independent risk factors for depressive symptoms; HIV-related enacted stigma was also associated with increased risk, warranting targeted services to support AYA-PHIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0956462420960602DOI Listing
March 2021

Longitudinal Analysis of Peripheral and Colonic CD161 CD4 T Cell Dysfunction in Acute HIV-1 Infection and Effects of Early Treatment Initiation.

Viruses 2020 12 11;12(12). Epub 2020 Dec 11.

U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.

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

Download full-text PDF

Source
http://dx.doi.org/10.3390/v12121426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764746PMC
December 2020

Minimal detection of cerebrospinal fluid escape after initiation of antiretroviral therapy in acute HIV-1 infection.

AIDS 2021 04;35(5):777-782

Yale School of Medicine, New Haven, Connecticut, USA.

Objective: Despite suppression of HIV-1 replication in the periphery by antiretroviral therapy (ART), up to 10% of treated individuals have quantifiable HIV-1 in the CSF, termed CSF escape. CSF escape may be asymptomatic but has also been linked to progressive neurological disease, and may indicate persistence of HIV in the central nervous system (CNS). CSF escape has not yet been assessed after initiation of ART during acute HIV-1 infection (AHI).

Design: Prospective cohort study.

Setting: Major voluntary counseling and testing site in Bangkok, Thailand.

Participants: Participants identified and initiated on ART during AHI who received an optional study lumbar puncture at pre-ART baseline or after 24 or 96 weeks of ART.

Main Outcome Measures: Paired levels of CSF and plasma HIV-1 RNA, with CSF greater than plasma HIV-1 RNA defined as CSF escape.

Results: Two hundred and four participants had paired blood and CSF sampling in at least one visit at baseline, week 24, or week 96. Twenty-nine participants had CSF sampling at all three visits. CSF escape was detected in 1/90 at week 24 (CSF HIV-1 RNA 2.50 log10 copies/ml, plasma HIV-1 RNA <50 copies/ml), and 0/55 at week 96.

Conclusion: Although levels of CSF HIV-1 RNA in untreated AHI are high, initiating treatment during AHI results in a very low rate of CSF escape in the first 2 years of treatment. Early treatment may improve control of HIV-1 within the CNS compared with treatment during chronic infection, which may have implications for long-term neurological outcomes and CNS HIV-1 persistence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAD.0000000000002786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7969409PMC
April 2021

Performance of a simple flow cytometric assay in diagnosing active tuberculosis.

Tuberculosis (Edinb) 2021 01 11;126:102017. Epub 2020 Nov 11.

The Kirby Institute for Infection and Immunity in Society, University of New South Wales, Sydney, Australia.

A flow cytometric assay measuring Mycobacterium tuberculosis-specific CD4 T-cell responses using co-expression of CD25/CD134 (OX40 assay) was explored as a diagnostic tool for active tuberculosis (TB) in a Thai population with and without HIV infection. Peripheral blood mononuclear cells (PBMC) obtained from 133 participants at TB diagnosis were cryopreserved. Seventy-six participants had a clinical diagnosis of TB which were confirmed by a positive culture. CD4 T-cell responses were measured after stimulation with a pool of overlapping peptides covering RD-1 antigens: CFP-10 + ESAT-6. The performance of the assay was also compared to the Xpert MTB/RIF assay. The overall sensitivity of the OX40 assay was 94.7% (95%CI 87.1-98.5); its specificity was 71.9% (95%CI, 58.5-83). The sensitivity of the OX40 assay among HIV-infected participants was 100% (95%CI, 88.8-100) with a specificity of 92.9% (95%CI, 66.1-99.8). OX40 assay performed particularly well in those with active TB and HIV infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tube.2020.102017DOI Listing
January 2021

Characteristics of suboptimal immune response after initiating antiretroviral therapy among people living with HIV with a pre-treatment CD4 T cell count <200 ​cells/mm in Thailand.

J Virus Erad 2020 Sep 19;6(3):100005. Epub 2020 Jul 19.

The HIV Netherlands Australia Thailand Research Collaboration (HIV-NAT), The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Background: Complete recovery of the CD4 T cell count is uncommon among chronically HIV-infected individuals with very low pre-treatment CD4 count. We studied the prevalence of chronically immune recovery and its associated factors including immune characteristics chronic HIV-infected Thais.

Methods: Treatment-naïve participants (n ​= ​375) from the HIV-NAT 006 cohort with a pre-treatment CD4 T cell count after initiating antiretroviral therapy (ART) and having achieved a suppressed viremia (HIV-RNA level ​< ​400 copies/mL) were retrospectively followed at the Thai Red Cross AIDS Research Centre, Bangkok, Thailand. Suboptimal immune recovery (SIR) was defined as having a CD4 T cell count <200 ​cells/mm for 3 years after ART initiation. A case-control sub-study matched for age, sex and pre-ART CD4 T cell count was conducted to compare immunological characteristics between SIR (n ​= ​17) and non-SIR (n ​= ​24) participants. Immunological biomarkers such as interleukin-7 (IL-7) and soluble CD14 (sCD14) and other covariates including cytomegalovirus (CMV) DNA level, baseline hemoglobin level, hepatitis B and C co-infections, and T cell subsets associated with immune activation and exhaustion were evaluated.

Results: Among 375 participants with pre-ART CD4 T cell counts < 200 ​cells/mm, the prevalence of SIR was 39.7%, 19.7% and 7.7% at years 1, 2 and 3 after starting ART, respectively. In a multivariate analysis, a pre-ART CD4 T cell count ≤100 ​cells/mm (adjusted odds ratio [aOR] 9.45, 95% CI 2.92-30.61, p ​< ​0.001), older age (aOR 1.07, 95% CI 1.01-1.13, p ​= ​0.029) and baseline HIV-RNA level (aOR 0.36, 95% CI 0.21-0.59, p ​< ​0.001) were independently associated with SIR at year 3 after ART initiation. In the matched case-control sub-study (cases ​= ​17, controls ​= ​24), there was a higher prevalence of hepatitis C co-infection (18.8% vs. 0%, p ​= ​0.05), lower sCD14 levels (mean, 6.23 vs. 6.27 log ​pg/mL, p ​= ​0.04), lower CD8 T cell counts (mean, 514 vs. 876, p ​= ​0.0003), lower CD4/CD8 T cell ratio (mean, 0.27 vs. 0.41, p ​= ​0.01) and higher expression of PD1 on CD8 T cells (74.2% vs. 65.1%, p ​= ​0.02) observed in SIR participants compared to their non-SIR counterparts at year 3 after ART initiation.

Conclusions: Nearly 10% of the study participants who had achieved virological suppression failed to recover a CD4 T cell count > 200 cells/mm after 3 years of ART which was with a very low pre-ART CD4 T cell count and older age. The long-term clinical outcomes of SIR participants need to be further explored.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jve.2020.100005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646671PMC
September 2020

A randomized trial of vorinostat with treatment interruption after initiating antiretroviral therapy during acute HIV-1 infection.

J Virus Erad 2020 Sep 18;6(3):100004. Epub 2020 Jul 18.

SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Objective And Design: A randomized, open-label pilot study in individuals treated with antiretroviral therapy (ART) since acute HIV infection (AHI) with a regimen including a histone deacetylase inhibitor to induce HIV from latency and control HIV replication during subsequent treatment interruption (TI).

Methods: Fifteen participants who initiated ART at AHI were randomized to vorinostat/hydroxychloroquine/maraviroc (VHM) plus ART (n ​= ​10) or ART alone (n ​= ​5). The VHM arm received three 14-day vorinostat cycles within 10 weeks before TI. ART was resumed for plasma viral load (VL) ​> ​1,000 HIV RNA copies/mL. Primary outcome was proportion of participants on VHM ​+ ​ART versus ART only with VL ​< ​50 copies/mL for 24 weeks after TI.

Results: Fifteen participants on ART (median: 178 weeks: range 79-295) enrolled. Two on VHM ​+ ​ART experienced serious adverse events. Fourteen participants underwent TI; all experienced VL rebound with no difference in time between arms: VHM ​+ ​ART (n ​= ​9) median: 4 weeks and ART only (n ​= ​5) median: 5 weeks. VHM induced a 2.2-fold increase in VL (p ​= ​0.008) by single-copy HIV RNA assay after the first cycle. Neopterin levels increased significantly following the first two cycles. After VHM treatment, the frequencies of peripheral blood mononuclear cells harboring total HIV DNA and cell-associated RNA were unchanged. All participants achieved VL suppression following ART re-initiation.

Conclusions: Administration of VHM increased HIV VL in plasma, but this was not sustained. VHM did not impact time to viral rebound following TI and had no impact on the size of the HIV reservoir, suggesting that HIV reservoir elimination will require alternative treatment strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jve.2020.100004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646672PMC
September 2020

Inflammatory Biomarkers Do Not Differ Between Persistently Seronegative vs Seropositive People With HIV After Treatment in Early Acute HIV Infection.

Open Forum Infect Dis 2020 Sep 26;7(9):ofaa383. Epub 2020 Aug 26.

HIV Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Persistent viral activity may cause enduring seropositivity and inflammation in treated people with HIV (PWH). We compared inflammatory biomarkers between early treated PWH who remained seronegative or seroconverted and found similar levels of D-dimer, soluble cluster of differentiation 14, C-reactive protein, and interleukin-6, indicating that seronegativity does not affect chronic inflammation in early treated PWH.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ofid/ofaa383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519777PMC
September 2020

Increased Burden of Concordant and Sequential Anogenital Human Papillomavirus Infections Among Asian Young Adult Women With Perinatally Acquired HIV Compared With HIV-Negative Peers.

Sex Transm Dis 2021 Mar;48(3):200-205

Department of Global Health, Amsterdam University Medical Centers, University of Amsterdam, and Amsterdam Institute for Global Health and Development.

Background: Youth with perinatally acquired HIV (YPHIV) are at higher risk for anogenital human papillomavirus (HPV) infection.

Methods: We enrolled a cohort of YPHIV and HIV-negative youth in Thailand and Vietnam, matched by age and lifetime sex partners, and followed them up for 144 weeks (to 2017). Participants had annual pelvic examinations with samples taken for HPV genotyping. Concordant infection was simultaneous HPV detection in multiple anogenital compartments (cervical, vaginal, anal); sequential infection was when the same type was found in successive compartments (cervicovaginal to/from anal). Generalized estimating equations were used to assess factors associated with concordant infection, and Cox regression was used to assess factors associated with sequential infection.

Results: A total of 93 YPHIV and 99 HIV-negative women were enrolled, with a median age of 19 years (interquartile range, 18-20 years). High-risk anogenital HPV infection was ever detected in 76 (82%) YPHIV and 66 (67%) HIV-negative youth during follow-up. Concordant anogenital high-risk HPV infection was found in 62 (66%) YPHIV versus 44 (34%) HIV-negative youth. Sequential cervicovaginal to anal high-risk HPV infection occurred in 20 YPHIV versus 5 HIV-negative youth, with an incidence rate of 9.76 (6.30-15.13) versus 2.24 (0.93-5.38) per 100 person-years. Anal to cervicovaginal infection occurred in 4 YPHIV versus 0 HIV-negative women, with an incidence rate of 1.78 (0.67-4.75) per 100 person-years. Perinatally acquired HIV was the one factor independently associated with both concordant and sequential high-risk HPV infection.

Conclusions: Children and adolescents with perinatally acquired HIV should be prioritized for HPV vaccination, and cervical cancer screening should be part of routine HIV care for sexually active YPHIV.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/OLQ.0000000000001294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867588PMC
March 2021

Determinants of suboptimal CD4 T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV-1 infection.

J Int AIDS Soc 2020 09;23(9):e25585

Yale School of Medicine, New Haven, CT, USA.

Introduction: Up to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm despite plasma viral suppression. We investigated the frequency and associations of suboptimal CD4 recovery after ART started during acute HIV infection (AHI).

Methods: Participants who started ART in Fiebig I to V AHI with ≥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 ), intermediate immune recovery (IIR; 350 ≤ CD4 < 500) and complete immune recovery (CIR; CD4 ≥ 500). Clinical and laboratory parameters were assessed at pre-ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints 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 (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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jia2.25585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507109PMC
September 2020

Central nervous system safety during brief analytic treatment interruption of antiretroviral therapy within four HIV remission trials: an observational study in acutely treated people living with HIV.

Clin Infect Dis 2020 Sep 11. Epub 2020 Sep 11.

Yale University, New Haven, Connecticut, USA.

Background: The central nervous system (CNS) is a likely reservoir of HIV, vulnerable to viral rebound, inflammation, and clinical changes upon stopping antiretroviral therapy (ART). It is critical to evaluate the CNS safety of studies using analytic treatment interruption (ATI) to assess HIV remission.

Methods: Thirty participants who started ART during acute HIV infection underwent CNS assessments across four ATI remission trials. ART resumption occurred with plasma viral load >1000 copies/mL. CNS measures included paired pre- vs. post-ATI measures of mood, cognitive performance, and neurologic examination, with elective cerebrospinal fluid (CSF) sampling, brain diffusion tensor imaging (DTI) and magnetic resonance spectroscopy (MRS).

Results: Median participant age was 30 years old and 29/30 were male. Participants' median time on ART prior to ATI was 3 years, and ATI lasted a median of 35 days. Post-ATI, there were no differences in median mood scores or neurologic findings and cognitive performance improved modestly. During ATI, a low level of CSF HIV-1 RNA was detectable in six of 20 participants with plasma viremia, with no group changes in CSF immune activation markers or brain DTI measures. Mild worsening was identified in post-ATI basal ganglia total choline MRS, suggesting an alteration in neuronal membranes.

Conclusion: No adverse CNS effects were observed with brief, closely-monitored ATI in participants with acutely treated HIV, except a MRS alteration in basal ganglia choline. Further studies are needed to assess CNS ATI safety in HIV remission trials, particularly for studies using higher thresholds to restart ART and longer ATI durations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa1344DOI Listing
September 2020

An Inflammatory Composite Score Predicts Mycobacterial Immune Reconstitution Inflammatory Syndrome in People with Advanced HIV: A Prospective International Cohort Study.

J Infect Dis 2021 Apr;223(7):1275-1283

National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

Background: Immune reconstitution inflammatory syndrome (IRIS) is a common cause of morbidity among people with human immunodeficiency virus (PWH) who initiate antiretroviral therapy (ART) with severe lymphopenia. Easily accessible tools that reliably predict emergence and elucidate pathogenesis of IRIS are needed to facilitate improved clinical management.

Methods: Plasma levels of biomarkers were measured before ART initiation in a large multinational cohort of ART-naive PWH with severe immunosuppression (CD4+ count <100 cells/mm3) in United States, Kenya, and Thailand. We performed a series of multiparametric analyses of inflammatory and clinical biomarkers and developed a composite score merging relevant biomarkers for use in a prediction model.

Results: We identified a distinct baseline inflammatory profile and changes in inflammatory networks among biomarkers in participants who subsequently developed mycobacterial or viral IRIS. We also developed a composite score incorporating biomarkers associated with IRIS (interleukin-6 [IL-6], IL-10, IL-27, sCD14, interferon-γ, tumor necrosis factor-α, hyaluronic acid, D-dimer, body mass index, and hemoglobin) that accurately predicted mycobacterial IRIS and death in this cohort.

Conclusions: Systemic inflammatory profiles in PWH with severe immunosuppression are predictive of IRIS. Composite scores for the prediction of mycobacterial IRIS and death could be useful for risk stratification in PWH and lymphopenia initiating ART.

Clinical Trials Registration: NCT00286767.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/infdis/jiaa484DOI Listing
April 2021

Parallel but connected: Nuances of conducting behavioral and social science research alongside ethically challenging HIV remission trials.

Contemp Clin Trials Commun 2020 Sep 16;19:100594. Epub 2020 Jun 16.

RTI International, Research Trialngle Park, NC, USA.

Collaborations between clinical investigators and behavioral and social science researchers (BSSR) produce many benefits, but also may generate challenges and complexities. Ongoing relationships between teams may affect the research carried out by the BSSR team and the way they interpret their findings. Here we describe our experiences conducting the HIV Remission ('Cure') Trials Decision-Making Study (DMS), in Thailand; these trials include potentially risky interventions and interruption of standard antiretroviral treatment, with little personal benefit. The DMS is a longitudinal study of the experiences of individuals recruited to such early-phase trials, and conducted alongside these trials. It originated in clinical investigators' concerns about the ability of those recruited to make voluntary and informed decisions about scientifically complex studies, and is led by an independent group of BSSR and ethics researchers. In conducting this study, we experienced three overarching challenges to achieving a successful and dynamic collaboration: managing emerging findings as data were collected alongside clinical trial participation; evolving interconnectedness and shifting partnership boundaries among investigators; and the process of incorporating new research questions. By describing these challenges, we provide experiential evidence on how to manage multidimensional aspects of these collaborations. We describe how our research teams came together as well as the challenges and opportunities we experienced along the way. Our aim is to raise awareness of the scientific, practical, and ethical complexities of establishing and maintaining this kind of broad multidisciplinary collaboration over time. By describing our experiences, we hope to advance an agenda for others who undertake similar partnerships.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.conctc.2020.100594DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322675PMC
September 2020

Continuous prophylactic ARV/ART since birth reduces seeding and persistence of the viral reservoir in vertically HIV-infected children.

Clin Infect Dis 2020 Jun 5. Epub 2020 Jun 5.

Centre de Recherche du CHUM and department of microbiology, infectiology and immunology, Université de Montréal, Canada.

Background: Early antiretroviral therapy (ART) restricts the size of the HIV reservoir in infants. However, whether antiretroviral (ARV) prophylaxis given to exposed vertically infected children exerts similar effects remains unknown.

Methods: We measured total and integrated HIV DNA, as well as the frequency of CD4 T-cells producing multiply-spliced RNA (msRNA) after stimulation (inducible reservoir) in vertically-infected Thai infants. Eighty-five infants were followed longitudinally for up to three years. We compared the size of the reservoir in children who received continuous prophylactic ARV since birth versus those who never received or discontinued prophylaxis before initiating ART. We used samples from a cross-sectional cohort of 37 Thai children who had initiated ART within 6 months of life to validate our findings.

Results: Before ART, levels of HIV DNA and the frequencies of cells producing msRNA were significantly lower in infants who received continuous prophylactic ARV since birth compared to those in whom prophylactic ARV was discontinued or never initiated (p<0.020 and p<0.001, respectively). Upon ART initiation, total and integrated HIV DNA levels decayed significantly in both groups (<0.01 in all cases). Interestingly, the initial differences in the frequencies of infected cells persisted during three years on ART. The beneficial effect of prophylaxis on the size of the HIV reservoir was confirmed in the cross-sectional study. Importantly, no differences were observed between children who discontinued prophylactic ARV before starting ART and those who delayed ART initiation without receiving prior prophylaxis.

Conclusions: Neonatal prophylactic ARV with direct transition to ART durably limits the size of the HIV reservoir.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa718DOI Listing
June 2020

Phyloanatomic characterization of the distinct T cell and monocyte contributions to the peripheral blood HIV population within the host.

Virus Evol 2020 Jan 27;6(1):veaa005. Epub 2020 Apr 27.

Department of Pathology, Immunology, and Laboratory Medicine, Emerging Pathogens Institute, University of Florida, Gainesville, FL 32601, USA.

Human immunodeficiency virus (HIV) is a rapidly evolving virus, allowing its genetic sequence to act as a fingerprint for epidemiological processes among, as well as within, individual infected hosts. Though primarily infecting the CD4+ T-cell population, HIV can also be found in monocytes, an immune cell population that differs in several aspects from the canonical T-cell viral target. Using single genome viral sequencing and statistical phylogenetic inference, we investigated the viral RNA diversity and relative contribution of each of these immune cell types to the viral population within the peripheral blood. Results provide evidence of an increased prevalence of circulating monocytes harboring virus in individuals with high viral load in the absence of suppressive antiretroviral therapy. Bayesian phyloanatomic analysis of three of these individuals demonstrated a measurable role for these cells, but not the circulating T-cell population, as a source of cell-free virus in the plasma, supporting the hypothesis that these cells can act as an additional conduit of virus spread.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ve/veaa005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185683PMC
January 2020

Preferential Infection of α4β7+ Memory CD4+ T Cells During Early Acute Human Immunodeficiency Virus Type 1 Infection.

Clin Infect Dis 2020 Dec;71(11):e735-e743

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

Background: Establishment of persistent human immunodeficiency virus type 1 (HIV-1) reservoirs occurs early in infection, and biomarkers of infected CD4+ T cells during acute infection are poorly defined. CD4+ T cells expressing the gut homing integrin complex α4β7 are associated with HIV-1 acquisition, and are rapidly depleted from the periphery and gastrointestinal mucosa during acute HIV-1 infection.

Methods: Integrated HIV-1 DNA was quantified in peripheral blood mononuclear cells obtained from acutely (Fiebig I-III) and chronically infected individuals by sorting memory CD4+ T-cell subsets lacking or expressing high levels of integrin β7 (β7negative and β7high, respectively). HIV-1 DNA was also assessed after 8 months of combination antiretroviral therapy (cART) initiated in Fiebig II/III individuals. Activation marker and chemokine receptor expression was determined for β7-defined subsets at acute infection and in uninfected controls.

Results: In Fiebig I, memory CD4+ T cells harboring integrated HIV-1 DNA were rare in both β7high and β7negative subsets, with no significant difference in HIV-1 DNA copies. In Fiebig stages II/III and in chronically infected individuals, β7high cells were enriched in integrated and total HIV-1 DNA compared to β7negative cells. During suppressive cART, integrated HIV-1 DNA copies decreased in both β7negative and β7high subsets, which did not differ in DNA copies. In Fiebig II/III, integrated HIV-1 DNA in β7high cells was correlated with their activation.

Conclusions: β7high memory CD4+ T cells are preferential targets during early HIV-1 infection, which may be due to the increased activation of these cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciaa497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778353PMC
December 2020

Brief Report: Group Sex and Methamphetamine Use Fuel an Explosive Epidemic of Hepatitis C Among HIV-Infected Men Who Have Sex With Men in Bangkok, Thailand.

J Acquir Immune Defic Syndr 2020 08;84(4):331-335

SEARCH, The Thai Red Cross AIDS Research Center, Bangkok, Thailand.

Background: Increased rates of hepatitis C virus (HCV) infection among HIV-infected men who have sex with men (MSM) and who deny injecting drugs have been reported in resource-rich settings.

Setting: We measured HCV prevalence and incidence in a predominantly MSM cohort with acute HIV infection in Bangkok, Thailand.

Methods: In 2009-2018, participants with acute HIV infection were enrolled into the SEARCH010/RV254 cohort. HCV antibody was measured at enrollment and at least once annually. Infection was confirmed with HCV RNA. Risk factors for HCV were analyzed by proportional hazards regression, with hazard ratios (HRs) calculated in a multivariable model.

Results: Of 573 participants, 94% were MSM, with a median age of 26 years (range 18-70 years). The prevalence of HCV antibody was 9 of the 573, or 1.6% [95% confidence interval (CI): 0.7% to 3.0%]. In 1883 person-years (PY) of follow-up, 39 incident cases were identified (20.7 per 1000 PY, 95% CI: 15.1 to 28.3). All incident cases were identified from 2014 onward, and incidence rose from a range of 7.5-11.4 per 1000 PY between 2014 and 2016 to 44.8 per 1000 PY in 2018 (P = 0.001). Most cases (97.4%) were MSM and denied injecting drugs (37 of the 39, 94.5%). In multivariate analysis, methamphetamine use [adjusted HR 2.33 (95% CI: 1.13 to 4.8), P = 0.022], group sex [adjusted HR 2.54 (95% CI: 1.26 to 5.12), P = 0.009], and a history of positive Treponema pallidum hemagglutination or rapid plasma reagin [adjusted HR 2.43 (95% CI: 1.22 to 4.85), P = 0.012] were significantly associated with incident HCV.

Conclusion: We report an HCV epidemic among this cohort of HIV-infected Bangkok-based MSM. Access to timely HCV diagnosis and treatment is needed to prevent morbidity and to decrease onward transmission.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/QAI.0000000000002356DOI Listing
August 2020

Safety and immunogenicity of Ad26 and MVA vaccines in acutely treated HIV and effect on viral rebound after antiretroviral therapy interruption.

Nat Med 2020 04 23;26(4):498-501. Epub 2020 Mar 23.

SEARCH, Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41591-020-0774-yDOI Listing
April 2020

Neutralizing antibody VRC01 failed to select for HIV-1 mutations upon viral rebound.

J Clin Invest 2020 06;130(6):3299-3304

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

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 μg/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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI134395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259993PMC
June 2020

Feasibility and safety of research sigmoid colon biopsy in a cohort of Thai men who have sex with men with acute HIV-1.

J Virus Erad 2020 Feb 20;6(1):7-10. Epub 2020 Feb 20.

SEARCH, The Thai Red Cross AIDS Research Centre, Bangkok, Thailand.

Background: The gut-associated lymphoid tissue (GALT) is a major reservoir of HIV-1 established early in acute HIV-1 infection (AHI). Sampling tissue from GALT can provide information about viral reservoirs and immune responses but may be complicated during AHI for reasons such as high viral replication, CD4 T cell depletion and immune activation. Risk of adverse events (AEs) associated with research sigmoid colon biopsies was assessed in participants with AHI in Bangkok, Thailand.

Methods: Between 2009 and 2016, 170 biopsies collected from the sigmoid colon were performed during AHI and at follow-up visits (median 24 weeks post AHI diagnosis). Adverse event incidence was evaluated, as well as the associations of procedure timing, repetition and clinical parameters with AE risk. Negative binomial regression models were used to calculate incidence rate ratios and 95% confidence intervals.

Results: Among 103 participants (median age of 27 years, 97.1% male, 96.1% men who have sex with men), 87 sigmoidoscopies were completed during AHI and 83 at a follow-up visit. Approximately 30 biopsies were obtained per procedure for assessment of colonic viral load and HIV-1 reservoir, immunohistochemistry or phenotypic assays. All 11 AEs were grade 1 (6.5%) and included abdominal discomfort ( = 5, 2.9%), mild rectal bleeding ( = 5, 2.9%) and difficulty passing stool ( = 1, 0.6%). Biopsy-related AE risk was not significantly associated with age, HIV-1 RNA, CD4 T cell count, or number and time of biopsy.

Conclusions: Complications of sigmoidoscopy with biopsy in participants with AHI were infrequent and mild. Longitudinal sampling of the sigmoid colon to evaluate the gut-associated HIV-1 reservoir can be safely performed as part of research studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043900PMC
February 2020

Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection.

Sci Transl Med 2020 03;12(533)

Centre de Recherche du CHUM and Department of Microbiology, Infectiology and Immunology, Université de Montréal, Montréal, QC H2X 0A9, Canada.

The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4 T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aav3491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293182PMC
March 2020

Plasmacytoid dendritic cells sense HIV replication before detectable viremia following treatment interruption.

J Clin Invest 2020 06;130(6):2845-2858

US Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

Plasmacytoid dendritic cells (pDCs) are robust producers of IFNα 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 IFNα in vitro, which correlated with decreased phosphorylation of IFN regulatory factory 7 (IRF7) and NF-κB. The levels of phosphorylated IRF7 and NF-κB inversely correlated with plasma IFNα2 levels, implying that pDCs were refractory to in vitro stimulation after IFNα 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI130597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260031PMC
June 2020

Resting-state neural signatures of depressive symptoms in acute HIV.

J Neurovirol 2020 04 27;26(2):226-240. Epub 2020 Jan 27.

Department of Psychological Sciences, University of Missouri-St. Louis, St. Louis, MO, USA.

Depressive symptoms are often elevated in acute and chronic HIV. Previous neuroimaging research identifies abnormalities in emotion-related brain regions in depression without HIV, including the anterior cingulate cortex (ACC) and amygdala. However, no studies have examined the neural signatures of depressive symptoms in acute HIV infection (AHI). Seed-based voxelwise resting-state functional connectivity (rsFC) for affective seed regions of interest (pregenual ACC, subgenual ACC [sgACC], bilateral amygdala) was computed for 74 Thai males with AHI and 30 Thai HIV-uninfected controls. Group analyses compared rsFC of ACC and amygdala seed regions between AHI and uninfected control groups. Within the AHI group, voxelwise regression analyses investigated the relationship between depressive symptoms and rsFC for these affective seed regions. Group analyses revealed alterations in rsFC of the amygdala in AHI versus uninfected controls. Depressive symptoms associated with decreased rsFC between ACC regions and posterior cingulate/precuneus, medial temporal, and lateral parietal regions in AHI. Symptoms of depression also correlated to increased rsFC between ACC regions and lateral prefrontal cortex, sgACC, and cerebellum in AHI. Similar to the ACC, depressive symptoms associated with decreased rsFC between amygdala and precuneus. Of blood biomarkers, only HIV RNA inversely correlated with rsFC between posterior sgACC and left uncus. We found that depressive symptoms in AHI associate with altered rsFC of ACC and amygdala regions previously implicated in depression. Longitudinal research in this cohort will be necessary to determine whether these early alterations in rsFC of affective network regions are related to persistent depressive symptoms after combination antiretroviral therapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s13365-020-00826-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261250PMC
April 2020