Davies, Z. to controls, no protection was seen in the Tat-only group, confirming previous reports for rhesus macaques. However, the multigenic group blunted acute viremia by approximately 1 log (= 0.017), and both the multigenic and Tat/Env groups reduced chronic viremia by 3 and 4 logs, respectively, compared to controls (multigenic, = 0.0003; Tat/Env, < 0.0001). The strikingly greater reduction in the Tat/Env group than in the multigenic group Nelotanserin (= 0.014) was correlated with Nelotanserin Tat and Env binding antibodies. Since prechallenge anti-Env antibodies lacked SHIV89.6P-neutralizing activity, other functional anti-Env and anti-Tat activities are under investigation, as is a possible synergy between the Tat and Env immunogens. AIDS vaccines have been under development for more than 20 years, yet an efficacious vaccine remains elusive (13). Since attenuated or inactivated human immunodeficiency virus (HIV) vaccines lack the requisite safety for human use, alternative strategies have focused on viral subunits as vaccine candidates. HIV Tat, the transactivator protein essential for viral infectivity and pathogenesis, is a logical choice for AIDS vaccine design. Tat is expressed early in the viral life cycle; consequently, Tat-specific immune responses elicited by prophylactic vaccines can potentially have a critical impact on HIV transmission and replication. Although Tat exhibits variability among HIV clades, key immunogenic and functional domains appear to be conserved (7, 40). In fact, cross-reactivity of anti-Tat antibodies in sera of patients from multiple clades has been reported (7). Nelotanserin Further, conformational antibodies elicited by the full-length Tat protein as an immunogen have shown reactivity against nonhomologous Tat variants (39). Tat may also serve therapeutic vaccine strategies. Tat is released by HIV-infected cells and taken up by bystander cells, where it is translocated to the nucleus (15). This extracellular Tat exhibits multiple functions contributing to immune suppression and pathogenesis (see reference 45 for a review). Among critical properties Nelotanserin are modulation of expression of Nelotanserin cellular genes, including transcription factors and cytokines, up-regulation of CCR5 and CXCR4 expression (24), and induction of apoptosis in T cells and macrophages (12, 28). Tat bound to cell surfaces has also been shown to enhance the infectivity of HIV and promote rapid spreading of the virus by interacting with gp120 (33). Anti-Tat antibody could inhibit this extracellular spread and help control effects on bystander cells. Paradoxically, Tat has recently been shown to exert an antiapoptotic effect on infected cells by modifying the expression of several cytoskeletal proteins (11). This may promote long-term survival of HIV-infected CD4+ T cells, turning them into reservoirs for continuous viral production. Cellular immune responses to Tat and other viral antigens could help eliminate such reservoirs. Tat also influences the immune system and acts as an adjuvant. The Tat protein is known to alter major histocompatibility complex (MHC) class I expression on the cell surface (26) and helps facilitate MHC class I presentation of antigens (16, 38) by modifying the immunoproteasome (18, 47). Tat enhances cellular immune responses Gata2 to coadministered antigens (59) and exhibits autoadjuvanticity by eliciting antibody responses in the absence of an exogenous adjuvant (25). Thus, Tat should be a potent immunogen. In fact, both Tat vaccines and native Tat expressed during HIV infection are immunogenic, and the immune responses elicited appear to contribute to protection. Both anti-Tat antibodies and Tat-specific cytotoxic T lymphocytes have been associated with slow progression to AIDS in infected individuals (46, 48, 53, 56), and Tat-specific cytotoxic T lymphocytes have been associated with control of viral replication during the acute phase of simian immunodeficiency virus (SIV) infection (2). Notably, phase I clinical trials of a native Tat vaccine have established safety and immunogenicity for both uninfected and HIV-infected volunteers, including development of Tat antibodies in all subjects and Tat-specific cellular immune responses in more than 80% of the volunteers (14, 14a). In support of targeting Tat as a vaccine immunogen, Tat-based vaccines, both the native protein and plasmid DNA bearing vaccine was ineffective in protecting rhesus macaques against intravenously administered SHIV89.6P (30). However, the combination of Tat with.