Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 132, Issue 10, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI156063
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Funding
- amfAR IMPACT [109222]
- NIH [UM1AI126611, P51OD011092, U42OD010426]
- National Cancer Institute, NIH [HHSN261200800001E, 75N91019D00024]
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Inhibiting mTOR can decrease the proliferation of CD4(+)TM cells, but chronic mTOR inhibition alone or in combination with T cell activation is not sufficient to disrupt the stability of the SIV reservoir.
Proliferation of latently infected CD4(+)T cells with replication-competent proviruses is an important mechanism contributing to HIV persistence during antiretroviral therapy (ART). One approach to targeting this latent cell expansion is to inhibit mTOR, a regulatory kinase involved with cell growth, metabolism, and proliferation. Here, we determined the effects of chronic mTOR inhibition with rapamycin with or without T cell activation in SIV-infected rhesus macaques (RMs) on ART. Rapamycin perturbed the expression of multiple genes and signaling pathways important for cellular proliferation and substantially decreased the frequency of proliferating CD4(+) memory T cells (TM cells) in blood and tissues. However, levels of cell-associated SIV DNA and SIV RNA were not markedly different between rapamycin-treated RMs and controls during ART. T cell activation with an anti-CD3LALA antibody induced increases in SIV RNA in plasma of RMs on rapamycin, consistent with SIV production. However, upon ART cessation, both rapamycin and CD3LALA-treated and control-treated RMs rebounded in less than 12 days, with no difference in the time to viral rebound or post-ART viral load set points. These results indicate that, while rapamycin can decrease the proliferation of CD4(+) TM cells, chronic mTOR inhibition alone or in combination with T cell activation was not sufficient to disrupt the stability of the SIV reservoir.
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