Development of an effective vaccine against HIV-1 is an important goal of AIDS research. Progress toward this goal is evident, but full protection has not yet been achieved. We are testing the hypothesis that Tat protein of HIV-1 will be a valuable component in a complex HIV vaccine. This protein has both transcriptional and immune-suppressing activities; some of its functions are believed due to extracellular Tat that is released from infected cells and acts on both infected and uninfected cells to promote disease. Vaccine studies in rhesus macaques confirmed that immunity to Tat can attenuate infection, but these studies have not yet provided compelling evidence for widespread clinical studies with Tat vaccines. In these animal studies a heterologous immunization was used, in that the Tat sequence in the vaccine did not match the Tat sequence found in the challenge virus. Experiments proposed here will test the hypothesis that a homologous immunization of macaques will provide superior protection in a virulent challenge model. The experimental plan proposes an immunogenicity study to assess qualitative and quantitative measures of humoral and cellular responses to Tat protein. One goal is to map B-cell epitopes uin Tat. We will use the full length 101 amino acid Tat homologous to the challenge virus SHIV89.6PD. The previous heterologous immunization studies used a truncated 86 amino acid sequence obtained from a different virus strain. A virus challenge study follows the immunogenicity analysis, and will directly compare homologous versus heterologous immunization. Challenged animals will be monitored to detect rapidly replicating viruses. Sequence analysis of Tat genes from these viruses may identify escape mutations that enable growth in the presence of antibody to Tat protein. It is important to improve the efficacy of Tat immunization in macaques, in order to justify clinical studies in man. Improvements might come from altered methods for antigen delivery, different adjuvants, or selecting optimal antigens. We consider the choice of optimal antigens to be the most important issue at present, and our studies will compare Tat proteins differing in both content and length, to show whether homologous immunization affords superior protection. The Tat immunization studies also provide new information on the biology of this unusual protein, and may help to confirm its broader role in the pathogenesis of AIDS.
| Tikhonov, Ilia; Ruckwardt, Tracy J; Berg, Shannon et al. (2004) Furin cleavage of the HIV-1 Tat protein. FEBS Lett 565:89-92 |
| Ruckwardt, Tracy J; Tikhonov, Ilia; Berg, Shannon et al. (2004) Sequence variation within the dominant amino terminus epitope affects antibody binding and neutralization of human immunodeficiency virus type 1 Tat protein. J Virol 78:13190-6 |
| Tikhonov, Ilia; Ruckwardt, Tracy J; Hatfield, Glen S et al. (2003) Tat-neutralizing antibodies in vaccinated macaques. J Virol 77:3157-66 |
| Yang, Yida; Tikhonov, Ilia; Ruckwardt, Tracy J et al. (2003) Monocytes treated with human immunodeficiency virus Tat kill uninfected CD4(+) cells by a tumor necrosis factor-related apoptosis-induced ligand-mediated mechanism. J Virol 77:6700-8 |
