Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Lal KG

PROVIDER: S-EPMC7764746 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Lal Kerri G KG Phuang-Ngern Yuwadee Y Suhkumvittaya Suchada S Leeansyah Edwin E Alrubayyi Aljawharah A Dias Joana J Waickman Adam A Kim Dohoon D Kroon Eugène E Pinyakorn Suteeraporn S Eller Leigh Anne LA Maciel Milton M Rerknimitr Rungsun R Chomchey Nitiya N Phanuphak Nittaya N de Souza Mark S S MSS Nitayaphan Sorachai S Ake Julie A JA Vasan Sandhya S Robb Merlin L ML Ananworanich Jintanat J Sandberg Johan K JK Schuetz Alexandra A Eller Michael A MA Paquin-Proulx Dominic D

Viruses 20201211 12

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 acu ...[more]

PMID: 33322496

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Project description:BackgroundIt is unknown if extremely early initiation of antiretroviral therapy (ART) may lead to long-term ART-free HIV remission or cure. As a result, we studied 2 individuals recruited from a pre-exposure prophylaxis (PrEP) program who started prophylactic ART an estimated 10 days (Participant A; 54-year-old male) and 12 days (Participant B; 31-year-old male) after infection with peak plasma HIV RNA of 220 copies/mL and 3,343 copies/mL, respectively. Extensive testing of blood and tissue for HIV persistence was performed, and PrEP Participant A underwent analytical treatment interruption (ATI) following 32 weeks of continuous ART.Methods and findingsColorectal and lymph node tissues, bone marrow, cerebral spinal fluid (CSF), plasma, and very large numbers of peripheral blood mononuclear cells (PBMCs) were obtained longitudinally from both participants and were studied for HIV persistence in several laboratories using molecular and culture-based detection methods, including a murine viral outgrowth assay (mVOA). Both participants initiated PrEP with tenofovir/emtricitabine during very early Fiebig stage I (detectable plasma HIV-1 RNA, antibody negative) followed by 4-drug ART intensification. Following peak viral loads, both participants experienced full suppression of HIV-1 plasma viremia. Over the following 2 years, no further HIV could be detected in blood or tissue from PrEP Participant A despite extensive sampling from ileum, rectum, lymph nodes, bone marrow, CSF, circulating CD4+ T cell subsets, and plasma. No HIV was detected from tissues obtained from PrEP Participant B, but low-level HIV RNA or DNA was intermittently detected from various CD4+ T cell subsets. Over 500 million CD4+ T cells were assayed from both participants in a humanized mouse outgrowth assay. Three of 8 mice infused with CD4+ T cells from PrEP Participant B developed viremia (50 million input cells/surviving mouse), but only 1 of 10 mice infused with CD4+ T cells from PrEP Participant A (53 million input cells/mouse) experienced very low level viremia (201 copies/mL); sequence confirmation was unsuccessful. PrEP Participant A stopped ART and remained aviremic for 7.4 months, rebounding with HIV RNA of 36 copies/mL that rose to 59,805 copies/mL 6 days later. ART was restarted promptly. Rebound plasma HIV sequences were identical to those obtained during acute infection by single-genome sequencing. Mathematical modeling predicted that the latent reservoir size was approximately 200 cells prior to ATI and that only around 1% of individuals with a similar HIV burden may achieve lifelong ART-free remission. Furthermore, we observed that lymphocytes expressing the tumor marker CD30 increased in frequency weeks to months prior to detectable HIV-1 RNA in plasma. This study was limited by the small sample size, which was a result of the rarity of individuals presenting during hyperacute infection.ConclusionsWe report HIV relapse despite initiation of ART at one of the earliest stages of acute HIV infection possible. Near complete or complete loss of detectable HIV in blood and tissues did not lead to indefinite ART-free HIV remission. However, the small numbers of latently infected cells in individuals treated during hyperacute infection may be associated with prolonged ART-free remission.

Dataset Information

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

Publications

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

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