The human T leukemia virus type 1 (HTLV-1) and its genetic counterpart, HTLV-2, are the first-described human retroviruses. Unlike human immunodeficiency virus (HIV-1), infections with HTLV-1 and HTLV-2 are generally silent and asymptomatic for the entire lifetime of an individual. The differential pathology seen between HIV-1 and HTLV-1 and HTLV-2 is most likely attributable to differences in viral accessory genes regulating viral replication, latency, and transport within the host cell. In the case of HTLV-1 and HTLV-2, the transcriptional activating proteins, known as Tax1 and Tax2, are essential for viral replication, but are also cellular promoters via the CREB and NF:B pathways. The in vitro activity of the HTLV-1 Tax1 protein has been evaluated extensively, especially in the context of its ability to function as an oncoprotein. Tax2 seems to lack this ability, which may account in part for the low pathogenecity of HTLV-2. Tax2 has additionally been reported to exhibit poor transactivation of both CREB and NF:B. Nonetheless, preliminary experiments conducted in our laboratory indicate that Tax2 protein expressed in E. coli (or in stably transduced Jurkat cells) is a potent inducer of beta chemokines by peripheral blood mononuclear cells (PBMCs), and was observed to down-regulate CCR5 co-receptor expression and improve PBMC viability and lymphoproliferative capacity. Additionally, Tax2 was shown to inhibit HIV-1 p24 antigen release in HIV-1 infected PBMCs and lymphoid cells. Hypothesis: HTLV-2 and its regulatory gene product, Tax2, have the potential to modify innate host immune responses though increased lymphocyte viability and proliferation, induction of beta chemokines, and down-regulation of CC-chemokine receptors. The resultant effects could alter host responses during co- infection with other pathogens, including HIV-1.
Specific Aims : (1) To confirm and validate the in vitro function of Tax2, wild type HTLV-2 (wtHTLV-2) will be compared with a Tax2-deficient HTLV-2 infectious clone ( TaxHTLV-2) with respect to their ability to affect PBMC proliferative capacity and elaboration of the beta chemokines. As a subaim, relative levels of beta chemokine expression in CD4+ vs. CD8+ T cell subsets will be compared. (2) To determine a mechanism of Tax2-mediated-induction of antiviral chemokines by comparing the ability of a recombinant Tax2 protein with a panel of Tax2 mutants. Mutant proteins will include alterations in the NF-KB activating region, CREB binding region, and nuclear localization region. (3) To implicate a possible dominant role of the HTLV-2 Tax2 protein as a possible immunomodulator during HIV-1/HTLV-2 co- infection. The overall goal of this research is to develop an understanding of the role of Tax2 in modulating lymphocyte function in HTLV-2 infected individuals, and to implicate its role in modifying HIV-1 infection in patients with HIV-1/HTLV-2 co-infections. The project explores a novel approach of examining the potential of an accessory protein of one virus (HTLV-2) to alter the biologic life cycle of a second, related virus (HIV-1) in the host cell reservoirs. We expect that the proposed research will advance our understanding of the dynamics of retroviral infections which affect thousands of Veteran's nationwide.
Relevance of the proposed research to veterans health and/or healthcare issues: The HIV epidemic has had a major impact on the VA healthcare system [www.hiv.va.gov/vahiv?page=prin-data-2005]. Since 1998, the VA has tracked the care provided to patients with HIV disease through the Immunology Case Registry (ICR). Data for the ICR are drawn from the VA's electronic medical record system, which includes a broad range of information on clinical condition and health care utilization. There were an estimated of 26,000 HIV infected veterans enrolled at VA facilities for treatment during FY2005. Many HIV infected veterans are reluctant to adhere to HAART therapy because of concerns related to toxicity. For these reasons, any new strategies for therapy associated with lower rates of toxicity and treatment failure are critically needed for HIV infected individuals. The proposed studies will focus on exploring possible strategies for immune based therapy of HIV infected patients.