Rapamycin limits CD4+ T cell proliferation in simian immunodeficiency virus-infected rhesus macaques on antiretroviral therapy

J Clin Invest. 2022 May 16;132(10):e156063. doi: 10.1172/JCI156063.


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.

Keywords: AIDS/HIV; Homeostasis; T cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Retroviral Agents / pharmacology
  • Anti-Retroviral Agents / therapeutic use
  • CD4-Positive T-Lymphocytes
  • Cell Proliferation
  • HIV Infections* / drug therapy
  • Macaca mulatta / genetics
  • RNA
  • Simian Acquired Immunodeficiency Syndrome*
  • Simian Immunodeficiency Virus*
  • Sirolimus / pharmacology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / pharmacology
  • Viral Load
  • Virus Replication


  • Anti-Retroviral Agents
  • RNA
  • TOR Serine-Threonine Kinases
  • Sirolimus