Background:  In our long-term studies of simian immunodeficiency virus_mac (SIV_mac)239 pathogenesis in the Chinese rhesus macaques (Ch rh) AIDS model, Ch rh progressed slowly to AIDS compared to Indian-origin rhesus (Ind rh). We followed up the first passage of 10 SIV_mac239-infected Ch rh for 5 years. Six Ch rh developed AIDS in 19~27 mo, which was slower than most Ind rh (3~12 mo.).The mechanisms that limit SIV pathogenesis in Ch rh are unknown. One possibility is that SIV_mac is less well-adapted in this subspecies. To test this hypothesis, 3 Ch rh (DT52, DT56, and DT92) were inoculated with the plasma from one Ch rh at the time of AIDS.

Methods:  Versant HIV RNA 3.0 Assay (bDNA) for plasma SIV loads, flow cytometry for intestinal/peripheral lymphocyte phenotyping, and ElISpot for IFN-g cytoxic T lymphocyte (CTL).

Results:  Compared with the first passage of SIV to Ch rh, these 3 Ch rh had similar levels of CD4, CD8 cells after acute infection. However, the plasma viral loads peaked at day7, which was earlier than the first passage Ch rh and earlier than SIV in Ind rh. Intestinal memory CD4⁺CCR5⁺ cells rapidly decreased in the acute phase of infection in all 3 animals, and the intestinal effector cells index (% CD4 cells x % CD4⁺CD45RA-CCR5⁺) of DT52, DT56, and DT92 were 0.08, 0.24, and 0.02, respectively, compared to 14.7, 19.5, and 35 before infection. The index by day 60 slightly rebounded, with 0.59, 0.9, and 1.8 of each animal. Interestingly, we observed that in the first passage in 10 Ch rh and the second passage in 3 Ch rh, animals with more memory CD4⁺CCR5⁺ cells before infection had the capability to restore these cells at the chronic phase and were AIDS-free for 5 years. Thus far, DT52 and DT56 developed AIDS in a shorter period of time (6 mo) compared to the first passage animals. DT92 remains alive with the viral load < 125 copies/mL and a normal CD4/CD8 ratio. Interferon-g ELISpot assay showed that DT52 had no detectable CTL responses, DT56 had responses to env at days 42, 90, and 180 after infection. Interestingly, DT92 had responses to gag at days 42 and 90, and multiple genes (env, gag, pol, tat and rev) responses at day 180 after infection, suggesting that multiple gene response is necessary for suppression of SIV. The third passage of SIV infection is underway for 4 Ch rh to expand our observations in the second SIV passage in Ch rh.

Conclusions:  Passage of SIV_mac increased the virus virulence. Infected Ch rh developed AIDS more quickly. Immunophenotyping of Ch Rh MHC is needed for the simian immunodeficiency virus_mac pathogenesis in this macaque subspecies.

Keywords: Pathogenesis; Immunology; Virology