It is now clear that the mucosa of the rectum, gut and vagina of AIDS patients contain HIV infected cells, and that colorectal cell lines can be infected in vitro, indicating that the sexual transmission of HIV is not dependent on the introduction of virus into the blood stream. Particularly if infection through the mucosa is the primary route of HIV infection, it will be necessary to develop immunization strategies which induce immunity at mucosal sites. Systemic immunization is rarely effective in this respect, and mucosal immunity is most often achieved through direct immunization of mucosally-associated lymphoid tissues. Previous studies by this group have shown that female macaques which are systematially primed and mucosally boosted with whole inactivated SIV vaccine in biodegradable microspheres exhibit specific antibodies in their cervico-vaginal secretions and resist vaginal challenge. In this component of the NCVDG SIV virus-like particles (VLPs), rgp130 and DNA expression vectors will be microencapsulated. These vaccines, plus recombinant SIV-poliovirus mini-replicons, will be immunologically evaluated in mice for their effectiveness as systemic and mucosal immunogens in preparation for their testing in the macaque mucosal challenge model. In parallel, microencapsulated HIV VLPs, rgp120, DNA expression vectors and HIV-poliovirus mini-replicons will be evaluated so that those approaches judged most promising on the basis of macaque testing are immediately available for advancement into the chimpanzee model of heterosexual transmission. Immune sera and mucosal secretions from the mice and macaques will be evaluated for their levels and isotype distribution of anti-SIV/HIV and virus neutralizing antibodies. ELISPOT assays will be used to quantitate the number and isotype distribution of specific antibody secreting cells in the spleens and gut lamina propria of mice and the blood mononuclear cells of macaques. In addition, CMI responses by the murine spleen and gut intraepithelial lymphocytes and macaque blood mononuclear cells will be evaluated. The specific objective of the component is to immunologically evaluate immunization approaches so that the most promising can be selectively advanced through macaque and chimpanzee testing.
