MOLECULAR BASIS OF MALT-INDUCED MUCOSAL IMMUNITY TO SIV

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The importance of the mucosal immune system against infectious diseases including AIDS is now well recognized since mucosal vaccine can induce antigen-specific immune responses in both mucosal and systemic compartments. Since HIV is primarily transmitted through sexual contact, the development of HIV vaccines which target genitourinary mucosal immunity is a high priority. The major goal of our studies continues to be the development of a nasal vaccine given with a molecular adjuvant which will elicit protective immune responses to simian immunodeficiency virus (SIV) in order to prevent sexual transmission of SIV in rhesus macaques. To do this, it will be necessary to elucidate the cellular and molecular basis for induction of immune responses to nasal-associated lymphoreticular tissues (NALT) and to determine if tonsils, adenoids and associated nasal lymphoid tissues are NALT in rhesus macaques. To facilitate these studies, we will use novel mutants of cholera toxin (mCTs) which retain adjuvant properties, but which lack ADP-ribosyl transferase activity and associated toxicity. To accomplish our overall goal, this grant is divided into five specific aims. Specifically, we will: 1) Immunize rhesus macaques with nasal vaccine containing SIV gp130 and mutants of CT (mCTs) which lack toxicity by which retain adjuvanticity for the induction of optimal mucosal and systematic antibody (Ab) responses; 2) Elucidate the nature of CD4- positive (CD4+) T helper (Th)- TYPE 1 (Th1) or Th2-type responses induced following nasal immunization with SIV vaccine and mCTs as adjuvant; 3) Test the hypothesis that rhesus macaque tonsils or adenoids represent mucosal inductive sites following nasal immunization. This analysis will involve surgical removal of macaque tonsils, adenoids and other nasal-associated tissues to assess SIV- specific T and B cell subsets following nasal immunization. In other studies removal of NALT will precede vasal vaccination to determine if they indeed represent inductive sites for immune responses to nasal vaccines; 4) Fully characterize NALT CD8+ cytotoxic T lymphocytes (CTLs) which are induced to SIV vaccine which mCT is used as adjuvant and for enhanced expression of chemokines in NALT; and 5) Determine if a nasal SIV vaccine given with NCTs as mucosal adjuvants will induce mucosal immunity for protection of female rhesus macaques from challenge via the reproductive tract. These proposed studies in rhesus macaques will provide new information regarding the cellular and molecular mechanisms for the induction of specific protective immunity by nasal immunization with mucosal vaccines containing SIV antigen and mCTs.