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

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

SUBMITTER: Kroon E

PROVIDER: S-EPMC9200151 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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

Kroon Eugène E Chottanapund Suthat S Buranapraditkun Supranee S Sacdalan Carlo C Colby Donn J DJ Chomchey Nitiya N Prueksakaew Peeriya P Pinyakorn Suteeraporn S Trichavaroj Rapee R Vasan Sandhya S Manasnayakorn Sopark S Reilly Cavan C Helgeson Erika E Anderson Jodi J David Caitlin C Zulk Jacob J de Souza Mark M Tovanabutra Sodsai S Schuetz Alexandra A Robb Merlin L ML Douek Daniel C DC Phanuphak Nittaya N Haase Ashley A Ananworanich Jintanat J Schacker Timothy W TW

The Journal of infectious diseases 20220601 12

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 i ...[more]

PMID: 35275599

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Project description:Mucosal mononuclear (MMC) CCR5+CD4+ T cells of the gastrointestinal (GI) tract are selectively infected and depleted during acute HIV-1 infection. Despite early initiation of combination antiretroviral therapy (cART), gut-associated lymphoid tissue (GALT) CD4+ T cell depletion and activation persist in the majority of HIV-1 positive individuals studied. This may result from ongoing HIV-1 replication and T-cell activation despite effective cART. We hypothesized that ongoing viral replication in the GI tract during cART would result in measurable viral evolution, with divergent populations emerging over time. Subjects treated during early HIV-1 infection underwent phlebotomy and flexible sigmoidoscopy with biopsies prior to and 15-24 months post initiation of cART. At the 2(nd) biopsy, three GALT phenotypes were noted, characterized by high, intermediate and low levels of immune activation. A representative case from each phenotype was analyzed. Each subject had plasma HIV-1 RNA levels <50 copies/ml at 2(nd) GI biopsy and CD4+ T cell reconstitution in the peripheral blood. Single genome amplification of full-length HIV-1 envelope was performed for each subject pre- and post-initiation of cART in GALT and PBMC. A total of 280 confirmed single genome sequences (SGS) were analyzed for experimental cases. For each subject, maximum likelihood phylogenetic trees derived from molecular sequence data showed no evidence of evolved forms in the GALT over the study period. During treatment, HIV-1 envelope diversity in GALT-derived SGS did not increase and post-treatment GALT-derived SGS showed no substantial genetic divergence from pre-treatment sequences within transmitted groups. Similar results were obtained from PBMC-derived SGS. Our results reveal that initiation of cART during acute/early HIV-1 infection can result in the interruption of measurable viral evolution in the GALT, suggesting the absence of de-novo rounds of HIV-1 replication in this compartment during suppressive cART.

Project description:BackgroundScaling up the antiretroviral (ART) program in Kenya has involved a strategy of using clinical guidelines coupled with decentralization of treatment sites. However decentralization pushes clinical responsibility downwards to health facilities run by lower cadre staff. Whether the organizational culture in health facilities affects the outcomes despite the use of clinical guidelines has not been explored. This study aimed to demonstrate the relationship between organizational culture and early mortality and those lost to follow up (LTFU) among patients enrolled for HIV care.Methods and materialsA stratified sample of 31 health facilities in Nairobi County offering ART services were surveyed. Data of patients enrolled on ART and LTFU for the 12 months ending 30th June 2013 were abstracted. Mortality and LTFU were determined and used to rank health facilities. In the facilities with the lowest and highest mortality and LTFU key informant interviews were conducted using a tool adapted from team climate assessment measurement questionnaire and competing value framework tool to assess organizational culture. The strength of association between early mortality, LTFU and organizational culture was tested.ResultsHalf (51.8%) of the 5,808 patients enrolled into care in 31 health facilities over the 12-month study period were started on ART. Of these 48 (1.6% 95% CI 0.8%-2.4%) died within three months of starting treatment, while a further 125 (4.2% 95% CI 2.1%-6.6%) were LTFU giving an attrition rate of 5.7% (95% CI 3.3%-8.6%). Tuberculosis was the most common comorbidity associated with high early mortality and high LTFU. Organizational culture, specifically an adhocratic type was found to be associated with low early mortality and low LTFU of patients enrolled for HIV care (P = 0.034).ConclusionThe use of ART clinical guidelines in a decentralized health systems are not sufficient to achieve required service delivery outcomes. The attrition rate above would mean 85,000 Kenyans missing care based on current HIV disease burden figures. Deliberate efforts to improve individual health facility leadership and inculcate an adhocratic culture may lower mortality and morbidity associated with initiating ART.

Project description:The zebrafish is extensively used as an animal model for human and fish diseases. However, our understanding of the structural organization of its immune system remains incomplete, especially the mucosa-associated lymphoid tissues (MALTs). Teleost MALTs are commonly perceived as diffuse and scattered populations of immune cells throughout the mucosa. Yet, structured MALTs have been recently discovered in Atlantic salmon (Salmo salar L.), including the interbranchial lymphoid tissue (ILT) in the gills. The existence of the ILT was only recently identified in zebrafish and other fish species, highlighting the need for in-depth characterizations of the gill-associated lymphoid tissue (GIALT) in teleosts. Here, using 3-D high-resolution microscopy, we analyze the GIALT of adult zebrafish with an immuno-histology approach that reveals the organization of lymphoid tissues via the labeling of T/NK cells with an antibody directed to a highly conserved epitope on the kinase ZAP70. We show that the GIALT in zebrafish is distributed over at least five distinct sub-regions, an organization found in all pairs of gill arches. The GIALT is diffuse in the pharyngeal part of the gill arch, the interbranchial septum and the filaments/lamellae, and structured in two sub-regions: the ILT, and a newly discovered lymphoid structure located along each side of the gill arch, which we named the Amphibranchial Lymphoid Tissue (ALT). Based on RAG2 expression, neither the ILT nor the ALT constitute additional thymi. The ALT shares several features with the ILT such as presence of abundant lymphoid cells and myeloid cells embedded in a network of reticulated epithelial cells. Further, the ILT and the ALT are also a site for T/NK cell proliferation. Both ILT and ALT show structural changes after infection with Spring Viraemia of Carp Virus (SVCV). Together, these data suggest that ALT and ILT play an active role in immune responses. Comparative studies show that whereas the ILT seems absent in most neoteleosts ("Percomorphs"), the ALT is widely present in cyprinids, salmonids and neoteleosts, suggesting that it constitutes a conserved tissue involved in the protection of teleosts via the gills.

Dataset Information

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

Publications

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

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