445 Innate and Adaptive Immune Responses to Infection of Macaques with Pathogenic and Attenuated SIV Strains P. N. Fultz*1, Q. Wei1, B. Tao1, P. Vance2, J. Lifson3, M. Piatak3, J. A. Hoxie2 1Univ of Alabama at Birmingham; 2Univ of Pennsylvania, Philadelphia; and 3Natl Cancer Inst, Frederick Cancer Res Devel Ctr, Frederick, MD
Background: During the early phases of HIV or SIV infections, little is known about the role of innate immunity, its effects on viral replication, and the transition to adaptive immunity. To determine whether there are differences in immune responses elicited by pathogenic versus attenuated viruses during infection of pig-tailed macaques, a comprehensive study was done using SIVmac239 and attenuated strains derived from it by mutating a conserved Tyr (Y-721) in an endocytosis signal (YRPV721-724) present in the Env cytoplasmic tail.
Methods: Four (4) groups of 3 pig-tailed macaques were inoculated IV with wild-type SIVmac239 or one of 3 Env-Y721 mutants. During the first days and wks after infection, levels of serum IFN-alpha and –gamma, activation (CD69) of CD3-CD16+ NK-cells and CD4+ and CD8+ T-cells, viral burdens, SIV antibody titers, and SIV Gag-specific proliferation and secretion of IFN-gamma (ELISpot) responses were evaluated.
Results: Animals with IFN-alpha or .gamma in blood at the time of inoculation cleared virus from plasma more rapidly. Increases in serum IFN-alpha peaked on day 10, but induction of low levels of IFN-gamma were detected only in the animals infected with WT SIVmac239. Neither cytokine was detected in animals that were infected with the most attenuated virus. CD3-CD16+ NK and CD4+ T-cells expressing CD69 increased in all animals within 5 to 10 days and remained elevated thereafter. However, those animals that had the lowest set points of plasma viremia had higher cellular responses than those animals that maintained high viral burdens. In progressor animals with high viral burdens and decreasing numbers of CD4+ T-cells, expression of CD16 on NK-cells in whole blood, but not on purified NK-cells, was lost.
Conclusions: After SIV infection, CD16+ NK and CD4+ T-cells were activated rapidly, serum IFN-alpha and –gamma correlated with lower viral loads and more rapid clearance of virus, and when levels of plasma RNA were stable, adaptive immune responses also correlated with maintenance of low viral burdens. In progressors, loss of ability to detect CD16 (FcgammaRIII required for ADCC) on NK-cells only in whole blood suggests that in blood access to CD16 is blocked, perhaps by antibodies or immune complexes, a finding that could explain, at least in part, impaired NK-cell activity during HIV infection.
