SHIV-C109p5 NHP induces rapid disease progression in elderly macaques with extensive GI viral replication

Deepanwita Bose, Nihar Deb Adhikary, Peng Xiao, Kenneth A. Rogers, Douglas E. Ferrell, Cecilia Cheng-Mayer, Theresa L. Chang, Francois Villinger

Research output: Contribution to journalArticlepeer-review

Abstract

CCR5-tropic simian/human immunodeficiencyviruses (SHIV) with clade C transmitted/founder envelopes represent a critical tool for the investigation of HIV experimental vaccines and microbicides in nonhuman primates, although many such isolates lead to spontaneous viral control post infection. Here, we generated a high-titer stock of pathogenic SHIV-C109p5 by serial passage in two rhesus macaques (RM) and tested its virulence in aged monkeys. The co-receptor usage was confirmedbefore infecting fivegeriatric rhesus macaques (four female and one male). Plasma viral loads were monitored by reverse transcriptase-quantitative PCR (RT-qPCR), cytokines by multiplex analysis, and biomarkers of gastrointestinal damage by enzyme-linked immunosorbent assay. Antibodies and cell-mediated responses were also measured. Viral dissemination into tissues was determined by RNAscope. Intravenous SHIV-C109p5 infection of aged RMs leads to high plasma viremia and rapid disease progression; rapid decrease in CD4+ T cells, CD4+CD8+ T cells, and plasmacytoid dendritic cells; and wasting necessitating euthanasia between 3 and 12 weeks post infection. Virus-specificcellular immune responses were detected only in the two monkeys that survived 4 weeks post infection. These were Gag-specificTNFα+CD8+, MIP1β+CD4+, Env-specificIFN-γ+CD4+, and CD107a+ T cell responses. Four out of fivemonkeys had elevated intestinal fatty acid binding protein levels at the viral peak, while regenerating islet-derived protein 3α showed marked increases at later time points in the three animals surviving the longest, suggesting gut antimicrobial peptide production in response to microbial translocation post infection. Plasma levels of monocyte chemoattractant protein-1, interleukin-15, and interleukin-12/23 were also elevated. Viral replication in gut and secondary lymphoid tissues was extensive.

Original languageEnglish
JournalJournal of Virology
Volume98
Issue number2
DOIs
StatePublished - Feb 2024
Externally publishedYes

Keywords

  • aging
  • AIDS
  • SHIV

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