Human immunodeficiency virus (HIV) and other lentiviruses infect cells independent of cell- cycle progression, but gammaretroviruses such as the murine leukemia virus (MLV) require passage of cells through mitosis. Previously it had been hypothesized that nuclear import properties of HIV elements were the major difference between HIV and other retroviruses that only enter the nuclear after mitosis. However, recent data indicates that the capsid (CA) protein, and not nuclear import proteins, is the major determinant of the ability of a retrovirus to infect non-dividing cells. Here, we will definitively test the model that CA is responsible for this important property of HIV and we will characterize the mechanism whereby CA influences early events in the viral lifecycle. In this proposal, HIV with specific mutations in HIV-1 CA will be characterized for their ability to infect non-dividing cells such as cell-cycle arrested cells, primary macrophages, and partially activated T cells. In particular, we will concentrate on a set of amino acids in the N-terminal domain of CA that preliminary data suggest have a profound effect on the ability of HIV to infect non- dividing cells. We will then determine the stage of the virus lifecycle that is affected these HIV-1 CA mutants by testing the hypothesis that uncoating is the rate-limiting step for infection of non-dividing cells, and by examining if the nuclear entry of viral nucleic acids is affected in non-dividing cells. Many of the cells that are targets of HIV in infected people, as well as the first cells thought to be infected upon transmission, turn out to be non-proliferating. Thus, the property of HIV to infect non-dividing cells allows it to spread to major viral reservoirs sites such as non-activated CD4+ T cells and terminally differentiated macrophages. The identification of the precise viral determinants that allow it access to non-dividing cells may present new drug targets against HIV.
| Yamashita, Masahiro; Emerman, Michael (2009) Cellular restriction targeting viral capsids perturbs human immunodeficiency virus type 1 infection of nondividing cells. J Virol 83:9835-43 |
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| Lin, Tsai-Yu; Emerman, Michael (2008) Determinants of cyclophilin A-dependent TRIM5 alpha restriction against HIV-1. Virology 379:335-41 |
| Yamashita, Masahiro; Perez, Omar; Hope, Thomas J et al. (2007) Evidence for direct involvement of the capsid protein in HIV infection of nondividing cells. PLoS Pathog 3:1502-10 |
