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CD32⁺CD4⁺ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice.

ABSTRACT: CD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4⁺ T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time. CD32⁺ memory CD4⁺ T cells were enriched in cell-associated (CA) HIV-1 DNA but not in CA HIV-1 RNA as compared to the CD32^-CD4⁺ fraction. Using multidimensional reduction analysis, several memory CD4⁺CD32⁺ T-cell clusters were identified expressing HLA-DR, TIGIT, or PD-1. Importantly, although tissue-resident CD32⁺CD4⁺ memory cells were enriched with translation-competent reservoirs, most of it was detected in memory CD32^-CD4⁺ T cells. Our findings support that CD32 labels highly activated/exhausted memory CD4⁺ T-cell subsets that contain only a small proportion of the translation-competent reservoir.

SUBMITTER: Adams P

PROVIDER: S-EPMC7753142 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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CD32+CD4+ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice.

Adams Philipp P Fievez Virginie V Schober Rafaëla R Amand Mathieu M Iserentant Gilles G Rutsaert Sofie S Dessilly Géraldine G Vanham Guido G Hedin Fanny F Cosma Antonio A Moutschen Michel M Vandekerckhove Linos L Seguin-Devaux Carole C

iScience 20201130 1

CD32 has raised conflicting results as a putative marker of the HIV-1 reservoir. We measured CD32 expression in tissues from viremic and virally suppressed humanized mice treated relatively early or late after HIV-1 infection with combined antiretroviral therapy. CD32 was expressed in a small fraction of the memory CD4+ T-cell subsets from different tissues in viremic and aviremic mice, regardless of treatment initiation time. CD32+ memory CD4+ T cells were enric ...[more]

PMID: 33364576

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Project description:Future HIV-1 curative therapies require a thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets during antiretroviral therapy (ART) and the cellular mechanisms that maintain this reservoir. Therefore, we sequenced near-full-length HIV-1 genomes and identified genetically-intact and genetically-defective genomes from resting naive, stem-cell memory, central memory, transitional memory, effector memory, and terminally-differentiated CD4+ T-cells with known cellular half-lives from 11 participants on ART. We find that a higher infection frequency with any HIV-1 genome was significantly associated with a shorter cellular half-life, such as transitional and effector memory cells. A similar enrichment of genetically-intact provirus was observed in these cells with relatively shorter half-lives. We found that effector memory and terminally-differentiated cells also had significantly higher levels of expansions of genetically-identical sequences, while only transitional and effector memory cells contained genetically-intact proviruses that were part of a cluster of identical sequences. Expansions of identical sequences were used to infer cellular proliferation from clonal expansion. Altogether, this indicates that specific cellular mechanisms such as short half-life and proliferative potential contribute to the persistence of genetically-intact HIV-1. IMPORTANCE The design of future HIV-1 curative therapies requires a more thorough understanding of the distribution of genetically-intact HIV-1 within T-cell subsets as well as the cellular mechanisms that maintain this reservoir. These genetically-intact and presumably replication-competent proviruses make up the latent HIV-1 reservoir. Our investigations into the possible cellular mechanisms maintaining the HIV-1 reservoir in different T-cell subsets have revealed a link between the half-lives of T-cells and the level of proviruses they contain. Taken together, we believe our study shows that more differentiated and proliferative cells, such as transitional and effector memory T-cells, contain the highest levels of genetically-intact proviruses, and the rapid turnover rate of these cells contributes to the expansion of genetically-intact proviruses within them. Therefore, our study delivers an in-depth assessment of the cellular mechanisms, such as cellular proliferation and half-life, that contribute to and maintain the latent HIV-1 reservoir.

Dataset Information

CD32⁺CD4⁺ memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice.

Publications

CD32<sup>+</sup>CD4<sup>+</sup> memory T cells are enriched for total HIV-1 DNA in tissues from humanized mice.

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