It is becoming increasing clear that protection against lentiviral infections and associated disease must include the presence of cell- mediated immune (CMI) responses in addition to appropriate levels of virus- specific neutralizing antibodies. However, our knowledge about the nature and quality of lentivirus CMI, derived from a large body of experimental and clinical findings, suggests that antigen-specific immune responses are orchestrated, to a large extent, by an interregulated complex network of multi-lineage cells and their products such as cytokines. Recent data from the laboratory of Shearer et al. suggest that there is a sequential loss of antigen-specific, allospecific, and polyclonal mitogen response of PBMC post HIV-1 infection, which corresponds with progression to disease. Our laboratory has basically confirmed this finding in SlVsmm-infected rhesus macaques. Additional evidence suggests that a shift from TH- to TH-2 specific immune response appears to correlate with disease progression in both human HIV-1 and SIV infection. These distinct lineages of T cells (THI vs TH2) exist in both CD4+ and CD8+ T cells, based on the secretion of a spectrum of overlapping and distinct set of cytokines. The rationale for the studies outlined in this proposal was provided by the fact that such cytokines cross-regulate the activation of each functional subset, and that each subset requires, besides the T-cell l receptor/MHC-peptide interaction, the involvement of a set of accessory/co-stimulatory molecules (CSM's) and cell adhesion molecules (CAM's) to generate antigen-specific immune responses. Our lab has prepared reagents, assays, and techniques to detect and quantitate the nonhuman primate equivalents of human cytokines, CSM's, and CAM's. In addition, we have established collaborative ties and have available a valuable set of cryopreserved cell samples from rhesus macaques prior to and post SIV infection. We will utilize these resources to determine whether the analysis of constitutive and induced cytokine profiles helps define distinct stages of SIV infection and/or distinguishes between protected and nonprotected recipients of SIV vaccines, naturally infected disease resistant and experimentally disease-susceptible monkeys, short-term and long-term survivors of experimental SIV infection, and systemic and mucosal SIV infection. In addition, it is our objective to prospectively examine the in vitro and in vivo effects of SIV infection on the constitutive and induced expression of CSM's and CAM's known to play a major role in the quality of CMI. Finally, it will be our objective to determine whether the sequential loss of immune responses (antigen recall, allo, and mitogen) in rhesus macaque post-SIV infection can be reconstituted in vitro with the use of cytokine(s) and/or the depletion/addition of appropriate subsets of autologous cells from the prior cryopreserved samples.
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