This laboratory studies the regulatory and structural genes of the human immunodeficiency virus (HIV) in order to understand the molecular basis for its pathogenicity. Because the virus requires host cell proteins to complete nearly every step of its life cycle, much of our focus is on identifying and characterizing host cell functions that are modified or utilized by viral proteins to serve specific functions for viral replication.

HIV infection of non-dividing cells: A unique property of HIV is its ability to infect non-dividing cells such as terminally differentiated macrophages. With most retroviruses, the cell must pass through mitosis for the viral DNA to enter the nucleus. HIV, however, has evolved such that there are multiple genetically separate elements that allow nuclear entry independent of the cell cycle. We are trying to determine how these different elements act to target sub-viral particles through the nuclear membrane, and how they affect viral tropism in macrophages. This work involves understanding the events that occur immediately after the virus has entered the cell in order to enter the nucleus.

HIV spread: HIV-1 grows with very rapid kinetics in vivo. We are characterizing the mechanisms that allow such rapid growth. In particular we had developed assays that mimic the rapid kinetics in vivo and have established that cell-to-to transmission is necessary for rapid viral spread. This transmission depends on the attachment of virus to dendritic cells that subsequently present viral complexes to T cells. We are studying the ways in which dendritic cells interact with HIV and the specific molecules that lead to virus adsorption on cell surfaces and cell adhesions. 

HIV and the cell cycle: HIV differs from other retroviruses in its interaction with the host cell. Unlike other retroviruses, which have little effect on cell growth, HIV encodes a protein that prevents infected cells from proliferating. This protein, called Vpr, prevents infected cells from entering mitosis by preventing the activation of the mitotic cyclin dependent kinase causing cells to arrest in G2 of the cell cycle. We are studying the molecular basis of Vpr action to understand how and why HIV interferes with the host cell cycle. We hope to understand the basis for the evolution of viral functions that impair the function of normal host T cells. 

HIV population genetics: HIV evolves rapidly both on a global scale and in individual infected people. The frequency of different variants in a population of viral species is dependent on both selective forces and random drift. We have developed tissue culture assays to measure the contribution of random drift on the evolution of HIV populations and compare it to the contributions of selective forces.

Gummuluru S, KewalRamani VN, Emerman M. Dendritic cell mediated viral transfer to T cells is required for HIV-1 persistence in the face of rapid cell turnover. J Virol 76:10692-701, 2002.

Dvorin JD, Bell P, Maul GG, Yamashita M, Emerman M, Malim MH. Reassessment of the roles of integrase and the central DNA flap in human immunodeficiency virus type-1 nuclear import. J Virol 76:12087-96, 2002.

McDonald D, Vodicka M, Lucero G, Svitkina TM, Borisy GG, Emerman M, Hope TJ. Visualization of the intracellular behavior of HIV in living cells. J Cell Biol 159:441-52, 2002.

Malim MH, Emerman M. HIV-1 sequence variation: drift, shift, and attenuation. Cell 104:469-72, 2001.