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Membrane glycoproteins encoded by human and murine retroviruses

We study membrane envelope glycoproteins encoded by human and animal retroviruses, the cell surface receptors with which they interact, and the mechanisms by which these interactions profoundly alter host cells. In collaboration with another laboratory, we have found that the cell surface receptors that mediate attachment and infection of many retroviruses are transporters of small essential metabolites. This investigation has enabled us to identify novel transporters and to use molecular genetic and biochemical methods to study the mechanisms for their functions in transport and in viral invasion of the cell. A recent major focus concerns the human immunodeficiency virus (HIV-1) and the mechanisms by which diverse HIV-1 membrane glycoproteins bind to cellular receptors and coreceptors (chemokine receptors) to cause infection and cytopathology.

Recently, a fascinating and important aspect of HIV-1 replication has come to light. Specifically, HIV-1 first binds to susceptible cells by attaching to the protein CD4 that occurs on T-lymphocytes and macrophages. However, for entry to occur the virus must secondarily bind to a coreceptor consisting of CXCR4 (on T-cells) or CCR5 (on macrophages). Initially, individuals become infected by a macrophage-tropic type of HIV-1 that uses CCR5, but the virus mutates in patients to generate T-cell tropic variants that use CXCR4. Recently, we found that infections by HIV-1 require assembly of a collar consisting of 4-6 coreceptors surrounding the virus. We have confirmed these findings and have developed sensitive new assays for coreceptor functions. We have proven that patient T-cell tropic strains of HIV-1 use CXCR4 as a coreceptor. And, by cloning coreceptor homologues from species such as monkey and mouse that are resistant to HIV-1 infection, and by carefully analyzing species differences in the amino acid sequences, we have begun to identify the specific coreceptor sites that interact with the virus during infection. The goal of our work is to understand the molecular mechanisms that control retroviral infections at cell surface membranes and to elucidate the factors that allow the viral membranes to specifically fuse with membranes of target cells.

Another major project in the lab concerns the role of the accessory gene vif that is essential for HIV-1 replication. We have found that human lymphocytes and macrophages have an innate mechanism for destroying HIV-1 and for curing the disease of AIDS, that the virus-encoded Vif protein neutralizes this cellular defense, and we have tentatively identified the cellular protein involved. We are trying to learn how this protein destroys HIV-1, and hope eventually to help develop a drug that would block Vif function and unleash this potent innate defense mechanism.
 

Recent Publications:

1. Platt EJ, Shea DM, Rose PP, Kabat D. Variants of human immunodeficiency virus type 1 that efficiently use CCR5 lacking the tyrosine-sulfated amino terminus have adaptive mutations in gp120, including loss of a functional N-glycan. J Virol. 2005 Apr;79(7):4357-68.

2. Platt EJ, Durnin JP, Kabat D. Kinetic factors control efficiencies of cell entry, efficacies of entry inhibitors, and mechanisms of adaptation of human immunodeficiency virus. J Virol. 2005 Apr;79(7):4347-56.

3. Rose KM, Marin M, Kozak SL, Kabat D. Transcriptional regulation of APOBEC3G, a cytidine deaminase that hypermutates human immunodeficiency virus. J Biol Chem. 2004 Oct 1;279(40):41744-9. Epub 2004 Aug 5.

4. Lavillette D, Kabat D. Porcine endogenous retroviruses infect cells lacking cognate receptors by an alternative pathway: implications for retrovirus evolution and xenotransplantation. J Virol. 2004 Aug;78(16):8868-77.

5. Rose KM, Marin M, Kozak SL, Kabat D. The viral infectivity factor (Vif) of HIV-1 unveiled. Trends Mol Med. 2004 Jun;10(6):291-7.