Pathogenicity and Mucosal Transmissibility of the R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 in Rhesus Macaques: Implications for Use in Vaccine Studies

Abstract

There is an urgent need to develop new pathogenic R5 simian/human immunodeficiency viruses (SHIVs) for the evaluation of candidate anti-HIV vaccines in nonhuman primates. Here, we characterize swarm SHIV_AD8 stocks, prepared from three infected rhesus macaques with documented immunodeficiency at the time of euthanasia, for their capacity to establish durable infections in macaques following inoculation by the intravenous (i.v.) or intrarectal (i.r.) route. All three viral stocks (SHIV_AD8-CE8J, SHIV_AD8-CK15, and SHIV_AD8-CL98) exhibited robust replication in vivo and caused marked depletion of CD4⁺ T cells affecting both memory and naïve CD4⁺ T lymphocyte subsets following administration by either route. Eleven of 22 macaques inoculated with the new SHIV_AD8 stocks were euthanized with clinical symptoms of immunodeficiency and evidence of opportunistic infections (Pneumocystis, Candida, and Mycobacterium). A single but unique founder virus, also present in the SHIV_AD8-CE8J swarm stock, was transmitted to two animals following a single i.r. inoculation of approximately 3 50% animal infectious doses, which is close to the threshold required to establish infection in all exposed animals. Because the three new SHIV_AD8 viruses are mucosally transmissible, exhibited tier 2 sensitivity to anti-HIV-1 neutralizing antibodies, deplete CD4⁺ T lymphocytes in vivo, and induce AIDS in macaques, they are eminently suitable as challenge viruses in vaccine experiments.