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292 Humoral and Cellular Immune Responses Induced by HIV Tat Protein Fails to Confer Protection against SHIV89.6p Infection
P. Silvera*1, J. Greenhouse1, J. Yalley-Ogunro1, M. W. Richardson2, J. Mirchandani2, E. G. Regulier2, C. Capini2, K. Khalili2, J.-F. Zagury3, M. Lewis1, and J. Rappaport2
1Southern Res. Inst., Frederick, MD, USA; 2Temple Univ., Philadelphia, PA, USA; and 3Univ. Pierre et Marie Curie, Paris, France
Background: The regulatory proteins Nef, Rev, and Tat of HIV-1, which are expressed early in the virus life cycle, are attractive targets for vaccine development, since the induction of effective immune responses targeting these early proteins should terminate virus replication. Here, we investigated whether vaccination with HIV-1 Tat or Tat toxoid would induce protective immunity in rhesus macaques.
Methods: At 0, 5, and 9 weeks, 4 groups of 4 rhesus macaques were immunized intramuscularly with 100 mug of HIV-1 IIIB or 89.6p Tat or Tat toxoid in the presence of Seppic ISA 51 (Oil) as adjuvant. Four control animals received adjuvant alone. A final boost was given at week 29, and 4 weeks later all animals were challenged by intravenous inoculation with 30 MID50 SHIV89.6p. Vaccine-induced immune responses were monitored by ELISA, T-lymphocyte proliferation, and intracellular cytokine assays using Tat or Tat toxoids as antigens. Outcome of challenge was assessed by virus isolation, viral load, and CD4+ T-cell count measurements, and seroconversion to the challenge virus.
Results: Vaccination induced high titer anti-Tat IgG in all immunized animals by week 7, but were somewhat lower in the 89.6p Tat group. Furthermore, we demonstrated that dominant B-cell epitopes reside in the amino- and carboxy-terminal regions, respectively. At week 11, Tat-specific T-helper responses were detected in 50% of immunized animals with S.I. values ranging from 23 to 105, and preliminary data indicate that T-cell epitopes are located within aa1(24 and aa37(66. In addition, Tat-specific IFN-gamma responses were detected in CD4+ and/or CD8+ T-lymphocyte subsets in 9 of 16 immunized animals at week 19. However, all animals became infected upon challenge with SHIV89.6p, and we observed no significant difference (p > 0.05) in viral loads and CD4+ T-cell counts between immunized and control animals.
Conclusions: Vaccination with HIV-1 IIIB or 89.6p Tat or Tat toxoid failed to confer protection despite robust anti-Tat humoral and cellular immune responses in some animals. Our findings suggest that Tat may be more effective as a vaccine when combined with other structural and regulatory proteins of HIV-1.
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