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

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 CD4(+)CCR6(+), Th1Th17 (CD4(+)CCR6(+)CCR4(-)CXCR3(+)), CD4(+)CCR6(+)CXCR3(-)CCR4(-), and CD4(+)CD32a(+) 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. Copyright (C) 2018 The Author(s). Published by Wolters Kluwer Health, Inc.