Macrophage-mediated delivery of HIV-1 Vaccine

St. Luke'S-Roosevelt Inst For Hlth Scis, New York NY

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Abstract

DESCRIPTION (provided by applicant): Highly active antiretroviral therapy (HA ART) has been effective in decreasing the incidence of Central Nervous System (CNS) complications due to HIV-1 infection. However, a significant proportion of patients on HAART still progress to HIV-associated dementia (HAD), indicating the need for more effective treatment of HIV-1 infection in the CNS. We have induced the synthesis of an endogenous cellular inhibitor of HIV- 1 replication in immortalized CD4vT lymphocytes by co-cultivation with peripheral blood lymphocytes (PBL) chronically infected with an attenuated HIV-1. Resistant cells secrete constitutively a soluble antiviral factor named HRF (HIV-1 Resistance Factor) that inhibits the replication of X4 and R5 laboratory strains of HIV-1 and patient isolates in vitro. After first review of this application, we identified hrf as a human homologue of arabidopsis thaliana glp-like binding protein. Our studies indicate that HRF interferes with NFkappaB transactivation of transcription of cellular genes and stops the LTR driven transcription of HIV-1 genes, The antiviral effect of HRF has been observed in vitro in several types of T cells by inhibition of HIV-1 LTR promoted expression of reporter genes and by inhibition of 4alpha-phorbol 12-myristate 13- acetate (PMA) induced expression of the latent HIV-1 in ACH-2 cells. Our recent preliminary data indicate that HRF also acts as an effective inhibitor of HIV-1 infection in primary human macrophages and fetal astrocytes. These observations suggest that HRF is a promising candidate for a new drug targeting both HIV-1 and NFKappaB-mediated induction of neuroinflammatory molecules such as TNF-alpha in the CNS. This exploratory project proposes: (1) to clone and express recombinant hrf; (2) To study the mechanism of HRF mediated inhibition of HIV-1 and TNF-alpha in vitro in macrophages;. The long-term goal of this project is to employ HRF as a novel inhibitor of both HIV replication and inflammation in the brain.