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43 Vaccine Protection against Functional Cytotoxic T Lymphocyte Abnormalities in Simian Human Immunodeficiency Virus-Infected Rhesus Monkeys
P. F. McKay*, J. E. Schmitz, M. J. Kuroda, D. H. Barouch, M. A. Lifton, C. E. Nickerson, D. A. Gorgone, and N. L. Letvin
Beth Israel Deaconess Med. Ctr., Harvard Med. Sch., Boston, MA, USA
Background: Accumulating evidence suggests that HIV-specific CD8+ cytotoxic T lymphocytes (CTL) are dysfunctional in HIV-infected individuals with progressive clinical disease.
Methods: Cytokine production by virus-specific CTL was assessed by cytoplasmic staining and flow cytometry in the rhesus monkey model for AIDS to determine its contribution to the functional impairment of CTL. CTL of animals that were infected with nonpathogenic virus isolates were compared with those from animals infected with pathogenic virus. A further comparison of cytokine production by CTL from both of these groups to CTL cytokine production from vaccinated animals that had been challenged with pathogenic virus and protected from disease progression was also performed. Statistical analyses were performed using the Wilcoxon Rank Sum test with Bonforoni adjustments of P values.
Results: CTL from monkeys infected with nonpathogenic isolates of simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) expressed high levels of interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-2 (IL-2) after in vitro exposure to a mitogen or a peptide representing a dominant virus-specific CTL epitope. However, similarly performed studies assessing these capabilities in CTL from monkeys infected with pathogenic immunodeficiency virus isolates demonstrated a significant dysfunction in the ability of the CTL to produce IL-2 and TNF-alpha. Importantly, CTL from vaccinated monkeys that effectively controlled the replication of a highly pathogenic SHIV isolate following challenge demonstrated a preserved capacity to produce these cytokines.
Conclusions: These experiments suggest that defects in cytokine production may contribute to CTL dysfunction in chronic HIV or SIV infection. Moreover, an AIDS vaccine that confers protection against clinical disease evolution in this experimental model also preserves the functional capacity of these CTL to produce both IL-2 and TNF-alpha.
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