Research Article: Proliferative memory SAMHD1low CD4+ T cells harbour high levels of HIV-1 with compartmentalized viral populations

Date Published: June 20, 2019

Publisher: Public Library of Science

Author(s): Lylia Hani, Antoine Chaillon, Marie-Laure Nere, Nicolas Ruffin, Joudy Alameddine, Maud Salmona, José-Luiz Lopez Zaragoza, Davey M. Smith, Olivier Schwartz, Jean-Daniel Lelièvre, Constance Delaugerre, Yves Lévy, Nabila Seddiki, Guido Silvestri.

http://doi.org/10.1371/journal.ppat.1007868

Abstract

We previously reported the presence of memory CD4+ T cells that express low levels of SAMHD1 (SAMHD1low) in peripheral blood and lymph nodes from both HIV-1 infected and uninfected individuals. These cells are enriched in Th17 and Tfh subsets, two populations known to be preferentially targeted by HIV-1. Here we investigated whether SAMHD1low CD4+ T-cells harbour replication-competent virus and compartimentalized HIV-1 genomes. We sorted memory CD4+CD45RO+SAMHD1low, CD4+CD45RO+SAMHD1+ and naive CD4+CD45RO-SAMHD1+ cells from HIV-1-infected patients on anti-retroviral therapy (c-ART) and performed HIV-1 DNA quantification, ultra-deep-sequencing of partial env (C2/V3) sequences and phenotypic characterization of the cells. We show that SAMHD1low cells include novel Th17 CCR6+ subsets that lack CXCR3 and CCR4 (CCR6+DN). There is a decrease of the % of Th17 in SAMHD1low compartment in infected compared to uninfected individuals (41% vs 55%, p<0.05), whereas the % of CCR6+DN increases (7.95% vs 3.8%, p<0.05). Moreover, in HIV-1 infected patients, memory SAMHD1low cells harbour high levels of HIV-1 DNA compared to memory SAMHD1+ cells (4.5 vs 3.8 log/106cells, respectively, p<0.001), while naïve SAMHD1+ showed significantly lower levels (3.1 log/106cells, p<0.0001). Importantly, we show that SAMHD1low cells contain p24-producing cells. Moreover, phylogenetic analyses revealed well-segregated HIV-1 DNA populations with compartmentalization between SAMHD1low and SAMHD1+ memory cells, and limited viral exchange. As expected, the % of Ki67+ cells was significantly higher in SAMHD1low compared to SAMHD1+ cells. There was positive association between levels of HIV-1 DNA and Ki67+ in memory SAMHD1low cells, but not in memory and naïve SAMHD1+ CD4+ T-cells. Altogether, these data suggest that proliferative memory SAMHD1low cells contribute to viral persistence.

Partial Text

The remarkable stability of the latent HIV-1 reservoir in the CD4+ memory T cell population prevents viral eradication with current antiretroviral therapy (c-ART). HIV-1 persistence is established through two major mechanisms: constitution of a small pool of lifelong latently infected CD4+ T-cells early in infection, ensuring the persistence of the virus for decades during c-ART [1,2] and residual replication of the virus at low levels in anatomical reservoirs in which c-ART may not diffuse [3]. Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to eliminate, or at least reduce the size of the HIV-1 reservoir [4].

Expanded CD4+ T cells with integrated HIV-1 can be a hurdle for achieving a cure as these cells represent a long-lived and persistent reservoir for the virus [38].

 

Source:

http://doi.org/10.1371/journal.ppat.1007868

 

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