Preventive and therapeutic vaccination against AIDS: safety, immunogenicity and efficacy of the HIV-1 Tat vaccine.
Int Conf AIDS 2000 Jul 9-14; 13:23 (abstract no.. LbOr25)
Ensoli B, Cafaro A, Caputo A, Maggiorella MT, Negri D, Pace M, Borsetti A, Baroncelli S, Fanales-Belasio E, Michelini Z, Macchia I, Ridolfi B, Sernicola L, Moretti S, Belli R, Corrias F, Verani P, Titti F, Butto S Instituto Superiore di Sanita, Laboratory of Virology, Rome, Italy. Fax: +39-06-49903002, E-mail: ensoli@iss.it.
Vaccine strategies based on the HIV/SIV envelope (Env) have failed to protect nonhuman primates against heterologous virus challenge due to the Env variability. Thus, new strategies aimed at controlling virus replication and disease onset should be developed to block the epidemic. We have chosen the HIV Tat protein because it is essential for HIV replication and infectivity, is immunogenic and highly conserved among HIV clades. Moreover, a Tat-immune response correlates with non-progression to AIDS. Therefore, safety, immunogenicity and efficacy trials were conducted in mice (N. 276), guinea pigs (N.48) and cynomolgus monkeys (N. 27) with both a biologically active Tat protein or tat DNA. The results indicate that both approaches are safe (no toxicity, local or systemic), immunogenic (antigen-specific antibody, T helper, cytotoxic and CD8-mediated antiviral responses) and induce a long-term (almost 2 years) protection against challenge with the highly pathogenic SHIV89.6P virus. In fact, 9/11 of the vaccinated monkeys that were already challenged showed no signs of virus replication in blood (negative p27 antigenemia, plasma viremia, cytoviremia, virus isolation) nor in lymph nodes (negative virus isolation and proviral DNA) nor CD4 T cell decline but only low and transient proviral DNA and SIV/HIV antibody titers in blood, and developed anti-Gag specific immune responses. In contrast, all control animals were highly infected with a profound CD4 T cell decline. Protection correlated (100%) with a Tat-specific Th1-type, CTL response and a CD8-mediated antiviral activity (Cafaro et al., Nat. Med. 1999, J. Med., Primatol. in press, and submitted; Goletti et al., submitted). Moreover, no toxicity, no increase of viral load nor a further CD4 T cell decline were observed in 4 SHIV89.6P-infected monkeys with AIDS upon vaccination with Tat. Since the Tat vaccine fully controlled virus replication and blocked disease onset, clinical trials will begin in Italy and Uganda.
Keywords: AEGIS, AIDS Vaccines, Acquired Immunodeficiency Syndrome, Gene Products, tat, SIV, HIV, HIV Antibodies, HIV Infections, Vaccination, Simian Acquired Immunodeficiency Syndrome, CD4-Positive T-Lymphocytes, Viral Load, Virus Replication, Macaca fascicularis, Clinical Trials, Italy, Uganda, human immunodeficiency virus type 1 Tat vaccine, Animal, Mice, immunology, virology, therapy, prevention & control, AIDS
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