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).

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

Starting antiretroviral therapy (ART) in Fiebig 1 acute HIV infection limits the size of viral reservoirs in lymphoid tissues, but does not impact time to virus rebound during a treatment interruption. To better understand why the reduced reservoir size did not increase the time to rebound we measured the frequency and location of HIV RNA+ cells in lymph nodes from participants in the RV254 acute infection cohort. HIV RNA+ cells were detected more frequently and in greater numbers when ART was initiated in Fiebig 1 compared to later Fiebig stages and were localized to the T-cell zone compared to the B-cell follicle with treatment in later Fiebig stages.

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

Background: The greater availability of different antiretroviral therapy regimens in developing countries may influence the emergence of transmitted drug resistance (TDR). People with acute HIV infection (AHI) represent the best opportunity for real-time monitoring of TDR. This study assessed the TDR prevalence trends over time in a Thai cohort of predominantly men who have sex with men (MSM) with AHI.

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

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.

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

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.

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

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.

Liver function test abnormalities in a longitudinal cohort of Thai individuals treated since acute HIV infection.

Introduction: Liver 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.

Methods: We 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.

Viral Blips After Treatment Initiation During Acute Human Immunodeficiency Virus Infection.

Transient viral blips ≥20 copies/mL were observed in 16.9% of acutely treated adults with HIV. Blip incidence increased from 0.

Switch to dolutegravir is well tolerated in Thais with HIV infection.

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.

Transmission dynamics among participants initiating antiretroviral therapy upon diagnosis of early acute HIV-1 infection in Thailand.

Objective: To assess transmission characteristics in a predominantly MSM cohort initiating antiretroviral therapy (ART) immediately following diagnosis of acute HIV-1infection (AHI).

Methods: A longitudinal study (2009-2017) was performed in participants with AHI (n = 439) attending a single clinic in Bangkok. Plasma samples obtained prior to ART were used to obtain HIV-1 pol sequences and combined with clinical and epidemiologic data to assess transmission dynamics (cluster formation and size) using phylogenetic analysis.

Rapid HIV RNA rebound after antiretroviral treatment interruption in persons durably suppressed in Fiebig I acute HIV infection.

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.

Acute Retroviral Syndrome Is Associated With High Viral Burden, CD4 Depletion, and Immune Activation in Systemic and Tissue Compartments.

Background: Many individuals with acute human immunodeficiency virus infection (AHI) experience acute retroviral syndrome (ARS), which is associated with adverse long-term clinical outcomes.

Methods: Participants presenting for voluntary human immunodeficiency virus (HIV) testing were enrolled during AHI in Bangkok, Thailand. ARS was defined by ≥3 qualifying signs/symptoms.

Viral kinetics in untreated versus treated acute HIV infection in prospective cohort studies in Thailand.

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.

Identification of Acute HIV-1 Infection by Hologic Aptima HIV-1 RNA Qualitative Assay.

The Hologic Aptima HIV-1 Qualitative RNA assay was used in a rigorous screening approach designed to identify individuals at the earliest stage of HIV-1 infection for enrollment into subsequent studies of cellular and viral events in early infection (RV 217/Early Capture HIV Cohort [ECHO] study). Volunteers at high risk for HIV-1 infection were recruited from study sites in Thailand, Tanzania, Uganda, and Kenya with high HIV-1 prevalence rates among the populations examined. Small-volume blood samples were collected by finger stick at twice-weekly intervals and tested with the Aptima assay.

Declining trend in transmitted drug resistance detected in a prospective cohort study of acute HIV infection in Bangkok, Thailand.

Introduction: As availability of antiretroviral therapy expands in developing countries, the risk for transmission of drug-resistant HIV also increases. Patients with acute HIV infection (AHI) provide an opportunity for real-time monitoring of transmitted drug resistance (TDR). SEARCH 010/RV 254 study is a prospective, longitudinal study of AHI.

Altered Memory Circulating T Follicular Helper-B Cell Interaction in Early Acute HIV Infection.

The RV254 cohort of HIV-infected very early acute (4thG stage 1 and 2) (stage 1/2) and late acute (4thG stage 3) (stage 3) individuals was used to study T helper- B cell responses in acute HIV infection and the impact of early antiretroviral treatment (ART) on T and B cell function. To investigate this, the function of circulating T follicular helper cells (cTfh) from this cohort was examined, and cTfh and memory B cell populations were phenotyped. Impaired cTfh cell function was observed in individuals treated in stage 3 when compared to stage 1/2.

Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection.

Background: The challenges of identifying acute HIV infection (AHI) have resulted in a lack of critical information on early AHI that constrains the development of therapeutics that are designed to eradicate HIV from the infected host.

Methods: AHI participants were recruited from the Thai Red Cross Anonymous Clinic in Bangkok, Thailand into the RV254/SEARCH010 protocol and categorised according to Fiebig stages as follows: Fiebig I (HIV-RNA+, p24 Ag-, HIV IgM-) and Fiebig II-IV (HIV-RNA+, p24 Ag + or -, HIV IgM- or +, Western blot- or indeterminate). Proviral and viral burden and immune activation levels were compared between Fiebig stage groups at the time of AHI.

Markers of HIV reservoir size and immune activation after treatment in acute HIV infection with and without raltegravir and maraviroc intensification.

Background: It is unclear whether intensification of standard highly active antiretroviral therapy (HAART) with entry and integrase inhibitors during acute HIV infection (AHI) could yield greater benefits in reducing markers for HIV reservoir size and immune activation.

Methods: Thai patients with Fiebig I-IV AHI were prospectively enrolled and offered treatment. They were randomised 1:1 to HAART (tenofovir/emtricitabine/efavirenz, =31) or megaHAART, a standard regimen intensified by raltegravir/maraviroc ( =31), during the first 24 weeks of therapy.

Impact of nucleic acid testing relative to antigen/antibody combination immunoassay on the detection of acute HIV infection.

Objective: To assess the addition of HIV nucleic acid testing (NAT) to fourth-generation (4thG) HIV antigen/antibody combination immunoassay in improving detection of acute HIV infection (AHI).

Methods: Participants attending a major voluntary counseling and testing site in Thailand were screened for AHI using 4thG HIV antigen/antibody immunoassay and sequential less sensitive HIV antibody immunoassay. Samples nonreactive by 4thG antigen/antibody immunoassay were further screened using pooled NAT to identify additional AHI.

Anogenital HIV RNA in Thai men who have sex with men in Bangkok during acute HIV infection and after randomization to standard vs. intensified antiretroviral regimens.

Introduction: HIV transmission risk is highest during acute HIV infection (AHI). We evaluated HIV RNA in the anogenital compartment in men who have sex with men (MSM) during AHI and compared time to undetectable HIV RNA after three-drug versus five-drug antiretroviral therapy (ART) to understand risk for onward HIV transmission.

Methods: MSM with AHI (n=54) had blood, seminal plasma and anal lavage collected for HIV RNA at baseline, days 3 and 7, and weeks 2, 4, 12 and 24.

High prevalence of transmitted drug resistance in acute HIV-infected Thai men who have sex with men.

: As use of antiretroviral therapy in Thailand increases, so does the potential for transmission of drug-resistant HIV. We describe the prevalence of WHO surveillance drug resistance mutations among 120 subjects who underwent genotypic testing during acute HIV infection in Bangkok, Thailand. In this cohort of predominantly men who have sex with men, we observed an overall transmitted drug resistance prevalence of 9.

Initiation of ART during early acute HIV infection preserves mucosal Th17 function and reverses HIV-related immune activation.

Mucosal Th17 cells play an important role in maintaining gut epithelium integrity and thus prevent microbial translocation. Chronic HIV infection is characterized by mucosal Th17 cell depletion, microbial translocation and subsequent immune-activation, which remain elevated despite antiretroviral therapy (ART) correlating with increased mortality. However, when Th17 depletion occurs following HIV infection is unknown.

A novel acute HIV infection staging system based on 4th generation immunoassay.

Background: Fourth generation (4thG) immunoassay (IA) is becoming the standard HIV screening method but was not available when the Fiebig acute HIV infection (AHI) staging system was proposed. Here we evaluated AHI staging based on a 4thG IA (4thG staging).

Findings: Screening for AHI was performed in real-time by pooled nucleic acid testing (NAT, n=48,828 samples) and sequential enzyme immunoassay (EIA, n=3,939 samples) identifying 63 subjects with non-reactive 2nd generation EIA (Fiebig stages I (n=25), II (n=7), III (n=29), IV (n=2)).

Extended evaluation of the virologic, immunologic, and clinical course of volunteers who acquired HIV-1 infection in a phase III vaccine trial of ALVAC-HIV and AIDSVAX B/E.

Background: The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection.

Methods: CD4(+) T-cell counts and HIV viral load (VL) were measured serially.

Impact of multi-targeted antiretroviral treatment on gut T cell depletion and HIV reservoir seeding during acute HIV infection.

Background: Limited knowledge exists on early HIV events that may inform preventive and therapeutic strategies. This study aims to characterize the earliest immunologic and virologic HIV events following infection and investigates the usage of a novel therapeutic strategy.

Methods And Findings: We prospectively screened 24,430 subjects in Bangkok and identified 40 AHI individuals.