Short- and Long-Term Clinical Outcomes in Rhesus Monkeys Inoculated with a Highly Pathogenic Chimeric Simian/Human Immunodeficiency Virus

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Abstract
A highly pathogenic simian/human immunodeficiency virus (SHIV), SHIV DH12R , isolated from a rhesus macaque that had been treated with anti-human CD8 monoclonal antibody at the time of primary infection with the nonpathogenic, molecularly cloned SHIV DH12 , induced marked and rapid CD4 + T cell loss in all rhesus macaques intravenously inoculated with 1.0 50% tissue culture infective dose (TCID 50 ) to 4.1 × 10 5 TCID 50 s of virus. Animals inoculated with 650 TCID 50 s of SHIV DH12R or more experienced irreversible CD4 + T lymphocyte depletion and developed clinical disease requiring euthanasia between weeks 12 and 23 postinfection. In contrast, the CD4 + T-cell numbers in four of five monkeys receiving 25 TCID 50 s of SHIV DH12R or less stabilized at low levels, and these surviving animals produced antibodies capable of neutralizing SHIV DH12R . 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 determined, but only the latter were statistically correlated to clinical outcome. The attenuating effects of reduced inoculum size were also observed when virus was inoculated by the mucosal route. Because the uncloned SHIV DH12R stock possessed the genetic properties of a lentivirus quasispecies, we were able to assess the evolution of the input virus swarm in animals surviving the acute infection by monitoring the emergence of neutralization escape viral variants.