ANIMAL-MODEL OF MUCOSALLY TRANSMITTED HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 DISEASE - INTRAVAGINAL AND ORAL DEPOSITION OF SIMIAN HUMAN IMMUNODEFICIENCY VIRUS IN MACAQUES RESULTS IN SYSTEMIC INFECTION, ELIMINATION OF CD4(+) T-CELLS, AND AIDS/

Chimeric simian/human immunodeficiency virus (SHIV) consists of the en v, vpu, tat, and rev genes of human immunodeficiency virus type 1 (HIV -1) on a background of simian immunodeficiency virus (SN), We derived a SHIV that caused CD4(+) cell loss and AIDS in pig-tailed macaques (S . V, Joag, Z, Li, L, Foresman, E. B, Stephens, L, J, Zhao, I, Adany, D , M, Pinson, H, M. McClure, and O, Narayan, J, Virol, 70:3189-3197, 19 96) and used a cell-free stock of this virus (SHIVKU-1) to inoculate m acaques by the intravaginal route, Macaques developed high virus burde ns and severe loss of CD4(+) cells within 1 month, even when inoculate d with only a single animal infectious dose of the virus by the intrav aginal route. The infection was characterized by a burst of virus repl ication that peaked during the first week following intravenous inocul ation and a week later in the intravaginally inoculated animals, Intra vaginally inoculated animals died within 6 months, with CD4(+) counts of <30/mu l in peripheral blood, anemia, weight loss, and opportunisti c infections (malaria, toxoplasmosis, cryptosporidiosis, and Pneumocys tis carinii pneumonia), To evaluate the kinetics of virus spread, we i noculated macaques intravaginally and euthanized them after 2, 4, 7, a nd 15 days postinoculation, In situ hybridization and immunocytochemis try revealed cells expressing viral RNA and protein in the vagina, ute rus, and pelvic and mesenteric lymph nodes in the macaque euthanized o n day 2, By day 4, virus-infected cells had disseminated to the spleen and thymus, and by day 15, global elimination of CD4(+) T cells was i n full progress, Kinetics of viral replication and CD4(+) loss were si milar in an animal inoculated with pathogenic SHIV orally, This provid es a sexual-transmission model of human AIDS that can be used to study the pathogenesis of mucosal infection and to evaluate the efficacy of vaccines and drugs directed against HIV-1.