IMMUNE RESPONSE TO HTLV NONSTRUCTURAL PROTEINS

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Human T cell leukemia virus type l (HTLV-I) is the etiologic agent of adult T cell leukemia, and HTLV-l associated myelopathy/tropical spastic paraparesis. Less than 5% of HTLV-l infected individuals develop either disease. The remaining 95% of infected individuals are asymptomatic carriers who are capable of transmitting infection. Evaluation of the immune response to HTLV-I in animal model systems has focused almost exclusively on the Gag and Env gene products. However, studies of infected humans have demonstrated significant, and in some cases predominant, humoral and cell-mediated. immune responses to the viral regulatory protein, Tax, and immunity to Tax has been associated with an increased efficiency of virus transmission. In the proposed studies, HTLV- l infected rabbits will be used to investigate Tax gene expression, immune responses and virus transmissibility in the carrier state. Our hypotheses are (i) that a portion of HTLV-I infected carriers express relatively high levels of Tax, transmit the virus efficiently, and display a strong immune response to Tax, and (ii) that immunity to Tax will slow or prevent progression of HTLV-I infection following viral challenge. The specific aims of the proposal are to: (1) Determine the kinetics of Tax gene expression after HTLV-l infection. Tax gene expression will be measured by quantitative RT-PCR analysis of RNA isolated from sequential blood and mucosal samples obtained from HTLV-I infected rabbits. (2) Determine the kinetics of humoral and cell mediated Tax-specific immune responses. Sequential blood and mucosal samples from HTLV-l infected rabbits will be used to measure the humoral and cell-mediated immune response to Tax. (3) Determine the relationship between Tax gene expression, immunity, and the degree of virus transmissibility. The presence of infectious virus will be determined by co-cultivation with uninfected PBMC, and p24 levels will be measured. The results of specific aims 1, 2, and 3 will be compared to evaluate whether gene expression correlates with virus transmissibility and immune responses to Tax. (4) Determine how prior immunization with Tax affects a subsequent HTLV-I infection. To evaluate a potential HTLV-l vaccine strategy, rabbits will be parenterally immunized with Tax and challenged with HTLV-l. Immune responses to Tax will be analyzed following immunization and challenge. Protection will be evaluated by co-cultivation and transfusion assays. The results of these studies will provide important new information regarding progression of, and host response to HTLV-l infection during the asymptomatic carrier state. In addition, a novel vaccine strategy based on anti-Tax immunity will be evaluated.