Our laboratory focuses on cellular factors which are involved in the activation of human retroviral transcription. In particular, we have focused on comparing the mechanism of activation of the HIV-2 enhancer to that of the HIV-1 enhancer. We have shown that the cis -acting elements responding to stimulation of the HIV-2 enhancer in activated T cells and monocytes differ significantly from those of HIV-1. In addition to the kB element, which is also present in the HIV-1 enhancer, we have identified two cis-acting elements which bind Elf-1, a member of the ets proto-oncogene family, and mediate activation of the HIV-2 enhancer. These elements are not present in the HIV-1 enhancer. Further, we have shown that an element proximal to one of the ets sites, designated pets, is also involved in activation of the HIV-2 enhancer. Pets binding proteins appear to be factors which interact with members of the ets family to stimulate human T cell leukemia virus type 1 (HTLV-1) as well as HIV-2 transcription. Mutation of either kB, the Elf-binding elements, or the pets site has a profound effect on HIV-2 enhancer function in T cells and monocytic cells. These data, as well as the fact that HIV-2, but not HIV-1, replication can be induced by stimulation of the T cell receptor, suggest that different co-factors may affect disease progression following infection with these viruses. Further, the more "fragile" nature of the HIV-2 enhancer may account, in part, for the observation that HIV-2 is less virulent than HIV-1.
Our laboratory is actively studying two proteins which interact with the HIV-2 enhancer: DEK and the GLI-2 protein. DEK is a protein which bears little resemblance to other known proteins. This protein has been associated with a translocation in a specific subtype of acute myelogenous leukemia and is known to be an autoantigen in certain cases of juvenile rheumatoid arthritis. Further, mice lacking DEK demonstrate an enhanced immune response to certain viral antigens. However, no biochemical or molecular function of DEK was previously described. We have now shown that DEK is a novel site-specific DNA-binding protein which recognizes the pets site of HIV-2. Studies are currently underway in the laboratory to identify the role of DEK in HIV-2 replication and in transcription, signal transduction, and oncogenesis. We have shown that GLI-2 is a strong activator of HIV-2 and HIV-1 transcription, while depressing the transcription of HTLV-1. GLI-2 can also synergize with the Tat transactivating protein of HIV. This synergy is TAR independent and appears to be mediated by the basal transcription machinery. A detailed molecular and biochemical analysis of the mechanism by which GLI-2, which is an important regulator of mammalian development, affects transcription is currently underway. The above studies have also lead us to begin work aimed at using gene therapy methods to treat HIV infection and autoimmune diseases. Other interests of the laboratory include the study of the effect of chemokines on HIV replication and the mechanism by which the LON protease influences gene expression.