Short- and long-term clinical outcomes in rhesus monkeys inoculated with ahighly pathogenic chimeric simian/human immunodeficiency virus

A highly pathogenic simian/human immunodeficiency virus (SHIV), SHIVDH12R, isolated from a rhesus macaque that had been treated with anti-human CD8 mo noclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIVDH12, induced marked and rapid CD4(+) T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture i nfective dose (TCID50) to 4.1 x 10(5) TCID(50)s of virus. Animals inoculate d with 650 TCID(50)s of SHIVDH12R or more experienced irreversible CD4(+) T lymphocyte depletion and developed clinical disease requiring euthanasia b etween weeks 12 and 23 postinfection, In contrast, the CD4(+) T-cell number s in four of five monkeys receiving 25 TCID(50)s of SHIVDH12R or less stabi lized at low levels, and these surviving animals produced antibodies capabl e of neutralizing SHIVDH12R. In the fifth monkey, no recovery from the CD4( +) T cell decline occurred, and the animal had to be euthanized. Viral RNA levels, subsequent to the initial peak of infection but not at peak viremia , correlated with the virus inoculum size and the eventual clinical course. Both initial infection rate constants, k, and decay constants, d, were det ermined, but only the latter were statistically correlated to clinical outc ome. The attenuating effects of reduced inoculum size were also observed wh en virus was inoculated by the mucosal route. Because the uncloned SHIVDH12 R stock possessed the genetic properties of a lentivirus quasispecies, we w ere able to assess the evolution of the input virus swarm in animals surviv ing the acute infection by monitoring the emergence of neutralization escap e viral variants.