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After more than 25 years of human immunodeficiency virus (HIV) research, a prophylactic vaccine able to control or prevent the worldwide spread of HIV/AIDS remains an elusive goal. Recent results in Thailand with the recombinant canary pox (ALVAC-HIV, vCP1521; Sanofi-Pasteur) prime-gp120 (AIDSVAX B/E) protein boost vaccine approach give us hope that such a vaccine is achievable (45). Nevertheless, the results from this trial as well as the disappointing outcome of the Step Study trial (7, 29, 46) vividly highlight the need to better understand the immune correlates of protection and the immune responses engendered by the diverse new vaccine technologies currently under evaluation (13,18,20,49). In the case of viral vectors, this is particularly critical, as the spectrum of immune responses elicited in animal models does not necessarily predict those eventually observed in human clinical trials and will require more thorough evaluations in order to identify the most predictive models. At the moment, nonhuman primate models, such as simian immunodeficiency virus (SIV) and simian-human immunodeficiency virus (SHIV) infection of macaques appear to be the most informative for guiding vaccine development (3,24,47,55), and more rigorous application of these models has begun to yield new and encouraging insights into protective immunity (5,19,27,56). Moreover, as most HIV transmissions occur through mucosal membranes, understanding the correlates of protection, following successful vaccinations, against mucosal challenge is of strong interest.Alphaviruses are positive-sense single-stranded 11.5-kb RNA viruses in the Togaviridae family. They are relatively simple enveloped viruses of approximately 60-nm diameter that have a cytoplasmic RNA-based life cycle and mature at the plasma membranes of infected cells. Recombinant alphavirus replicon particles used for vaccine applications are composed of a replicon vector that encodes the viral replicases (nonstructural proteins [NSPs]) and the vaccine antigen of interest and two packaging vectors that encode the major viral structural proteins (capsid and glycoproteins E1 and E2) required for particle formation. The chimeric (VEE/SIN) alpha-* Corresponding author. Mailing address: Novartis Vaccines and Diagnostics,

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Live attenuated lentivirus immunization is the only vaccine strategy that elicits consistent protection against intravaginal challenge with pathogenic simian immunodeficiency virus (SIV). To determine the mechanism of protection in rhesus monkeys infected with attenuated simian-human immunodeficiency virus (SHIV)89.6, a detailed analysis of SIV Gag-specific T-cell responses in several tissues including the genital tract was performed. Six months after SHIV infection, antiviral T-cell responses were rare in the cervix; however, polyfunctional, cytokine-secreting, and degranulating SIV Gag-specific CD4(+) T cells were consistently found in the vagina of the immunized macaques. SIV-specific CD8(+) T cells were also detected in the vagina, blood, and genital lymph nodes of most of the animals. Thus, an attenuated SHIV vaccine induces persistent antiviral T cells in tissues, including the vagina, where these effector T-cell responses may mediate the consistent protection from vaginal SIV challenge observed in this model.

In nonhuman primate models of acquired immunodeficiency syndrome, live attenuated lentiviruses provide the most reliable protection from systemic and mucosal challenge with pathogenic simian immunodeficiency virus (SIV). Although live attenuated lentiviruses may never be used in humans because of safety concerns, understanding the nature of the protective immune mechanisms induced by live attenuated vaccines in primate models will be useful for developing other vaccine approaches. Approximately 60% of rhesus macaques immunized with nonpathogenic simian-human immunodeficiency virus (SHIV) strain 89.6 are protected from infection or clinical disease after intravaginal (IVAG) challenge with pathogenic SIVmac239. The goal of the present study was to determine whether administration of Depo-Provera before IVAG challenge with SIV decreases the protective efficacy of infection with SHIV89.6. The rate of protection after IVAG challenge with SIVmac239 was significantly lower (P<.05), and the acute postchallenge plasma viral RNA levels were significantly higher (P<.006), in Depo-Provera-treated, SHIV89.6-immunized macaques than in Depo-Provera-naive, SHIV89.6-immunized macaques. In the primate model of sexual transmission of human immunodeficiency virus, treatment with progesterone before IVAG challenge with a pathogenic virus can decrease the efficacy of a model "vaccine."