Dataset Information

HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy.

ABSTRACT:

Background

The lungs were historically identified as one of the major anatomic sites for HIV replication in the pre-antiretroviral therapy (ART) era. However, their contribution to HIV persistence in individuals under suppressive ART remains understudied.

Design

We assessed HIV persistence and comprehensively characterized pulmonary mucosal CD4 T cells in HIV-infected (HIV) individuals receiving long-term suppressive ART versus uninfected participants.

Methods

Bronchoalveolar lavage (BAL), bronchial biopsies, and matched peripheral blood were obtained from n?=?24 HIV-infected adults receiving long-term suppressive ART (median: 9 years) and n?=?8 healthy volunteers without respiratory symptoms. HIV-DNA and cell-associated HIV-RNA were quantified by ultra-sensitive PCR, and lung mucosal CD4 T-cell subsets were characterized by multiparameter flow cytometry.

Results

The levels of HIV-DNA were 13-fold higher in total BAL cells compared to blood. Importantly, FACS-sorted CD4 T cells from BAL contained greater levels of HIV-DNA compared to peripheral CD4 T cells. BAL CD4 T cells in HIV individuals were characterized mostly by an effector memory phenotype, whereas naive and terminally differentiated cells were underrepresented compared to blood. Furthermore, BAL CD4 T cells expressed higher levels of immune activation (HLA-DR/CD38) and senescence (CD57) markers. Importantly, BAL was enriched in T-cell subsets proposed to be preferential cellular HIV reservoirs, including memory CD4CCR6, Th1Th17 (CD4CCR6CCR4CXCR3), CD4CCR6CXCR3CCR4, and CD4CD32a T cells.

Conclusion

The pulmonary mucosa represents an important immunological effector site highly enriched in activated and preferential CD4 T-cell subsets for HIV persistence during long-term ART in individuals without respiratory symptoms. Our findings raise new challenges for the design of novel HIV eradication strategies in mucosal tissues.

SUBMITTER: Costiniuk CT

PROVIDER: S-EPMC6200382 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy.

Costiniuk Cecilia T CT Salahuddin Syim S Farnos Omar O Olivenstein Ron R Pagliuzza Amélie A Orlova Marianna M Schurr Erwin E De Castro Christina C Bourbeau Jean J Routy Jean-Pierre JP Ancuta Petronela P Chomont Nicolas N Jenabian Mohammad-Ali MA

AIDS (London, England) 20181001 16

<h4>Background</h4>The lungs were historically identified as one of the major anatomic sites for HIV replication in the pre-antiretroviral therapy (ART) era. However, their contribution to HIV persistence in individuals under suppressive ART remains understudied.<h4>Design</h4>We assessed HIV persistence and comprehensively characterized pulmonary mucosal CD4 T cells in HIV-infected (HIV) individuals receiving long-term suppressive ART versus uninfected participants.<h4>Methods</h4>Bronchoalveol ...[more]

PMID: 30102653

Similar Datasets

Project description:UnlabelledThe ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection in ex vivo assays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy.ImportanceCurrent antiretroviral therapy is very effective in suppressing active HIV-1 replication but does not fully eliminate virally infected cells. The ability of HIV-1 to persist long term despite suppressive antiretroviral combination therapy represents a perplexing aspect of HIV-1 disease pathogenesis, since most HIV-1 target cells are activated, short-lived CD4 T cells. This study suggests that CD4 T helper cells with Th1/17 polarization have a preferential role as a long-term reservoir for HIV-1 infection during antiretroviral therapy, possibly because these cells may imitate some of the functional properties traditionally attributed to stem cells, such as the ability to persist for extremely long periods of time and to repopulate their own pool size through homeostatic self-renewal. These observations support the hypothesis that HIV-1 persistence is driven by small subsets of long-lasting stem cell-like CD4 T cells that may represent particularly promising targets for clinical strategies aiming at HIV-1 eradication and cure.

Dataset Information

HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy.

Background

Design

Methods

Results

Conclusion

Publications

HIV persistence in mucosal CD4+ T cells within the lungs of adults receiving long-term suppressive antiretroviral therapy.

Similar Datasets

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