INDUCTION OF KSHV REPLICATION BY HIV 1

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (Adapted from Applicant's abstract): KS is the most common neoplasm occurring in patients with AIDS. Kaposi's sarcoma-associated herpesvirus (KSHV) is universally present in Kaposi's sarcoma tissue and in a rare subset of non-Hodgkin' lymphomas termed primary effusion lymphomas (PEL). A causal role for KSHV in the pathogenesis of KS has been suggested by epidemiological data, and is supported by the presence of KSHV gene products, which can alter the cellular activation state, activate cell cycling, and inhibit apoptosis. HIV infection greatly increases the risk of KS development in KSHV-seropositive individuals. In a PEL cell culture-based model, HIV replication stimulates lytic phase replication and transmission of KSHV. The major goal of this research proposal is to determine the mechanism underlying the stimulation of KSHV replication by HIV. A second goal is to define the potential influence of KSHV gene products upon replication of HIV in the PEL cell model. To achieve these goals, the HIV gene product(s) required for stimulation of KSHV replication will first be determined. Proviruses with knockout mutations in key gene products will be analyzed in the HIV-PEL model for their ability to induce lytic KSHV replication. The role of HIV-1 Tat, Env, Vpr, and Nef in altering the replication of KSHV in the absence of other HIV gene products will be examined by expression of these gene products or controls within cells harboring KSHV in latent phase. Although HIV- and KSHV co-infected cells undergo lytic phase replication, a soluble factor released from HIV-infected PEL cells is also capable o stimulating KSHV lytic replication. The identity of this soluble factor will be pursued through measurement o released cellular cytokines, measurement of released HIV and KSHV gene products, and by biochemical purification techniques. HIV replication may act to induce lytic replication through the activation of an. immediate-early KSHV gene, KSHV Rta. The role of HIV infection in inducing transcriptional activation of KSHV Rta and of additional KSHV transcripts will be assessed in the HIV-infected PEL-cell model. The mechanism of HIV spread in two PEL cell lines will next be investigated, with an emphasis on identifying KSHV gene products, which facilitate transmission and replication of HIV. Finally, the effect of HIV infection upon KSHV lytic replication will be investigated in a model of primary monocyte-derived macrophage infected with KSHV and HIV. These studies have relevance to the pathogenesis of AIDS-KS, and may provide insights into interactions between HIV and KSHV, which occur in co-infected individuals.