Abstract
HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. Here, we show that cervical CD4+TRM display a unique repertoire of clusters of differentiation, with enrichment of several molecules associated with HIV infection susceptibility, longevity and self-renewing capacities. These protein profiles are enriched in a fraction of CD4+TRM expressing CD32. Cervical explant models show that CD4+TRM preferentially support HIV infection and harbor more viral DNA and protein than non-TRM. Importantly, cervical tissue from ART-suppressed HIV+ women contain high levels of viral DNA and RNA, being the TRM fraction the principal contributor. These results recognize the lower female genital tract as an HIV sanctuary and identify CD4+TRM as primary targets of HIV infection and viral persistence. Thus, strategies towards an HIV cure will need to consider TRM phenotypes, which are widely distributed in tissues.
Highlights
HIV viral reservoirs are established very early during infection
In order to confirm that CD69 expression in these human mucosal tissues defines cells compatible with a TRM profile reported by others[25,31,32], we first analyzed the expression of several transcriptional factors and surface proteins previously associated to TRM in a small group of samples
The gating strategy used for these analyses and examples of the expression of these markers in the CD69− or the CD69+ fraction of CD4+ T cells derived from cervical tissues are shown in Fig. 1a, b, respectively
Summary
HIV viral reservoirs are established very early during infection. Resident memory T cells (TRM) are present in tissues such as the lower female genital tract, but the contribution of this subset of cells to the pathogenesis and persistence of HIV remains unclear. The effector memory phenotype and the expression of CD30 have been associated to transcriptionally active infected cells[14,15] Most of these populations have been determined in blood, while in tissues is where the main reservoir resides. In ART-suppressed patients proviral DNA determined in cells obtained from ileum biopsies[16] or from bronchoalveolar lavage[17] is enriched compared to blood, and even CD4+ T cells from adipose tissue represent a niche of viral persistence[18] In macaque models these reservoirs are established within three days after infection[19] and target cells present in the initially infected tissues may have great relevance in the generation and persistence of these reservoirs
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