Resident memory T cells are a cellular reservoir for HIV in the cervical mucosa

Abstract

HIV viral reservoirs; Cervical mucosa; TRM

Reservorios virales de VIH; Mucosa cervical; TRM

Reservoris virals del VIH; Mucosa cervical; TRM

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.

This work was primarily supported by grants from the Spanish "Ministerio de Economia y Competitividad, Instituto de Salud Carlos III" (ISCIII, PI14/01235 and PI17/01470) and a fellowship award from the Dexeus foundation for women's health research to M.G., grants R21AI118411 and SAF2015-67334-R (from the Spanish Secretariat of Science and Innovation and FEDER funds) to M.J.B and grants from the ISCIII (PI14/01058 and PI17/00164) to J.G.P. M.G., M.J.B., and. J.G.P. are supported by the Spanish AIDS network Red Tematica Cooperativa de Investigacion en SIDA (RD16/0025/0007) M.G. is currently supported by the "Pla estrategic de recerca i innovacio en salut" (PERIS, SLT002/16/00353), from the Catalan government, while the Miguel Servet program from the ISCIII supports M.J.B. (CP17/00179) and J.G.P. (CP15/00014).