Immune Responses and Viral Persistence in Simian/Human Immunodeficiency Virus SHIV.C.CH848-Infected Rhesus Macaques

J Virol. 2021 Apr 12;95(9):e02198-20. doi: 10.1128/JVI.02198-20. Print 2021 Apr 12.

Abstract

Chimeric simian/human immunodeficiency viruses (SHIVs) are widely used in nonhuman primate models to recapitulate human immunodeficiency virus (HIV) infection in humans, yet most SHIVs fail to establish persistent viral infection. We investigated immunological and virological events in rhesus macaques infected with the newly developed SHIV.C.CH848 (SHIVC) and treated with combined antiretroviral therapy (cART). Similar to HIV/simian immunodeficiency virus (SIV) infection, SHIV.C.CH848 infection established viral reservoirs in CD4+ T cells and myeloid cells, accompanied by productive infection and depletion of CD4+ T cells in systemic and lymphoid tissues throughout SHIV infection. Despite 6 months of cART-suppressed viral replication, integrated proviral DNA levels remained stable, especially in CD4+ T cells, and the viral rebound was also observed after ART interruption. Autologous neutralizing antibodies to the parental HIV-1 strain CH848 were detected, with limited viral evolution at 5 months postinfection. In comparison, heterogenous neutralizing antibodies in SHIV.C.CH848-infected macaques were not detected except for 1 (1 of 10) animal at 2 years postinfection. These findings suggest that SHIV.C.CH848, a novel class of transmitted/founder SHIVs, can establish sustained viremia and viral reservoirs in rhesus macaques with clinical immunodeficiency consequences, providing a valuable SHIV model for HIV research.IMPORTANCE SHIVs have been extensively used in a nonhuman primate (NHP) model for HIV research. In this study, we investigated viral reservoirs in tissues and immune responses in an NHP model inoculated with newly generated transmitted/founder HIV-1 clade C-based SHIV.C.CH848. The data show that transmitted founder (T/F) SHIVC infection of macaques more closely recapitulates the virological and clinical features of HIV infection, including persistent viremia and viral rebound once antiretroviral therapy is discontinued. These results suggest this CCR5-tropic, SHIVC strain is valuable for testing responses to HIV vaccines and therapeutics.

Keywords: SHIV; autologous neutralizing Abs; autologous neutralizing Abs and evolution; evolution; persistent infection; viral reservoirs.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anti-Retroviral Agents / therapeutic use
  • Antibodies, Neutralizing / immunology
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / immunology
  • Disease Models, Animal*
  • HIV Infections* / drug therapy
  • HIV Infections* / immunology
  • HIV Infections* / virology
  • HIV-1
  • Humans
  • Macaca mulatta
  • Simian Acquired Immunodeficiency Syndrome* / drug therapy
  • Simian Acquired Immunodeficiency Syndrome* / immunology
  • Simian Acquired Immunodeficiency Syndrome* / virology
  • Simian Immunodeficiency Virus
  • Viral Load / drug effects
  • Viremia / drug therapy

Substances

  • Anti-Retroviral Agents
  • Antibodies, Neutralizing