PATHOGENESIS OF NEW SIVSMM LINEAGES IN RHESUS MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The intrinsic pathogenicity of SIVsmm in rhesus macaques (Rh) is significantly lower than widely believed. We showed that this new model of SIV infection in Rh is characterized by: slower progression to AIDS; stronger control of VLs; gradual loss of CD4+ T-cells in both periphery and intestine; partial immune restoration of target cells in the intestine. We investigated whether or not cellular immune responses were responsible for the less pathogenic outcome of Rh infection with primary SIVsmm isolates. Twenty-two Indian Rh were infected with 3 primary SIVsmm isolates. Plasma viral loads (VLs), humoral and cellular immune responses, dynamics of cytokines and chemokines in plasma and immunophenotypic markers were measured during acute and chronic SIVsmm infection. All SIVsmm strains replicated at high levels during primary infection. In 3 Rh (one in each group), peak VLs were lower than 10^6 SIVsmm RNA copies/ml. Set point VL levels during chronic infection were 2-4 log lower than those observed in Rh chronically infected with highly pathogenic SIVmac strains. Massive depletion of intestinal CD4+ T-cells was observed and was related to viral replication during the acute stage; its magnitude was not predictive of replication patterns during the chronic infection. IFN-gamma and IL-2 Elispot assays showed a strong and broadly directed SIV-specific cellular immune response targeting 4-7 SIV peptide pools, independent of the viral strain and of the same order of magnitude as those observed in Rh infected with SIVmac. During chronic SIVsmm infection, the T-cell immune activation levels were intermediate between highly pathogenic SIVmac infections and non-progressive infections in African hosts.