Pathogenesis Studies of Simian Immunodeficiency Virus Infection of Macaques

Hirsch, V.

Abstract

The major emphasis of this project was the study of SIV pathogenesis in experimentally- infected macaques, utilizing strains derived from sooty mangabeys (SIVsm) and African green monkeys (SIVagm). SIVsm clones derived from an immunodeficient macaque were employed to study viral factors contributing to the induction of AIDS. A study of SIVsm clones derived from the spleen of an immunodeficient SIV-infected pig-tailed macaque identified a region analogous to the V3 loop of HIV-1 envelope to be responsible for determining tropism. Naturally-occurring variation in this region determined whether viruses infected macaque lymphocytes and/or macrophages and this tropism appeared to be linked to pathogenicity. The degree of variation within the envelope of viruses within tissues of SIV-infected macaques was compared utilizing single stranded conformational poymorphism (SSCP) and sequence analysis. Virus populations within lymphoid tissues were highly heterogeneous whereas, distinct and homogeneous populations were observed in the brain and PBMC. A SIVagm strain (SIVagm9063) was isolated and molecularly cloned after experimental passage through a pig-tailed (PT) macaque. This isolate induced immunodeficiency in experimentally infected pig-tailed macaques but caused an asymptomatic infection of rhesus (RH) macaques and African green monkeys (AGM). An infectious, molecular clone produced a high viral load and reproduced the immunodeficiency syndrome in PT macaques. Probes for in situ hybridization were developed and analysis of tissues of PT macaques, RH macaques and AGM revealed significant diminution in viral load in the latter two species suggesting that disease was directly related to extent of infection. Treatment of SIV infected monkeys with an inhibitor of TNFalpha (pentoxyfilline) failed to alter the course of disease.

Funding Agency

• Agency: National Institute of Health (NIH)
• Institute: National Institute of Allergy and Infectious Diseases (NIAID)
• Type: Intramural Research (Z01)
• Project #: 1Z01AI000370-12
• Application #: 3746527
• Support Year: 12
• Fiscal Year: 1994

Institution

• Name: National Institute of Allergy and Infectious Diseases
• Country: United States

Publications

Sanders-Beer, Brigitte E; Eschricht, Magdalena; Seifried, Janna et al. (2012) Characterization of a monoclonal anti-capsid antibody that cross-reacts with three major primate lentivirus lineages. Virology 422:402-12

Kuwata, Takeo; Nishimura, Yoshiaki; Whitted, Sonya et al. (2009) Association of progressive CD4(+) T cell decline in SIV infection with the induction of autoreactive antibodies. PLoS Pathog 5:e1000372

Dang, Que; Goeken, Robert M; Brown, Charles R et al. (2008) Adaptive evolution of simian immunodeficiency viruses isolated from 2 conventional-progressor macaques with encephalitis. J Infect Dis 197:1695-700

Pandrea, Ivona; Apetrei, Cristian; Gordon, Shari et al. (2007) Paucity of CD4+CCR5+ T cells is a typical feature of natural SIV hosts. Blood 109:1069-76

Gautam, Rajeev; Carter, Anders Chase; Katz, Nathalia et al. (2007) In vitro characterization of primary SIVsmm isolates belonging to different lineages. In vitro growth on rhesus macaque cells is not predictive for in vivo replication in rhesus macaques. Virology 362:257-70

Nishimura, Yoshiaki; Igarashi, Tatsuhiko; Buckler-White, Alicia et al. (2007) Loss of naive cells accompanies memory CD4+ T-cell depletion during long-term progression to AIDS in Simian immunodeficiency virus-infected macaques. J Virol 81:893-902

Brown, Charles R; Czapiga, Meggan; Kabat, Juraj et al. (2007) Unique pathology in simian immunodeficiency virus-infected rapid progressor macaques is consistent with a pathogenesis distinct from that of classical AIDS. J Virol 81:5594-606

Kuwata, Takeo; Byrum, Russell; Whitted, Sonya et al. (2007) A rapid progressor-specific variant clone of simian immunodeficiency virus replicates efficiently in vivo only in the absence of immune responses. J Virol 81:8891-904

Kuwata, Takeo; Dehghani, Houman; Brown, Charles R et al. (2006) Infectious molecular clones from a simian immunodeficiency virus-infected rapid-progressor (RP) macaque: evidence of differential selection of RP-specific envelope mutations in vitro and in vivo. J Virol 80:1463-75

Pandrea, Ivona; Silvestri, Guido; Onanga, Richard et al. (2006) Simian immunodeficiency viruses replication dynamics in African non-human primate hosts: common patterns and species-specific differences. J Med Primatol 35:194-201