Publications (110) View all
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Chapter: Molecular Basis of Cell Cycle Dependent HIV-1 Replication
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ABSTRACT: Retroviruses show a strong cell cycle dependence for productive infection. For example, the onco-retrovirus murine leukaemia virus (MLV) requires proliferating host cells for productive infection (Temin, 1988; Varmus and Brown, 1989). This restriction appears to reflect an inability of viral DNA to localize to the host cell nucleus until the host cell enters mitosis (Roe, et al., 1993; Lewis, 1994 and Emerman, 1994). This dependence of onco-retroviruses for dividing cells is further illustrated by the poor transduction capacities of onco-retrovirus based retroviral vectors in non-dividing cell systems in vitro (miller, et al., 1990; Springett, et al., 1989).06/2011: pages 33-45; -
Article: HIV-1 infection requires a functional integrase NLS.
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ABSTRACT: HIV-1 is able to infect nondividing cells productively in part because the postentry viral nucleoprotein complexes are actively imported into the nucleus. In this manuscript, we identify a novel nuclear localization signal (NLS) in the viral integrase (IN) protein that is essential for virus replication in both dividing and nondividing cells. The IN NLS stimulates the efficient nuclear accumulation of viral DNA as well as virion-derived IN protein during the initial stages of infection but is dispensable for catalytic function. Because this NLS is required for infection irrespective of target cell proliferation, we suggest that interactions between uncoated viral nucleoprotein complexes and the host cell nuclear import machinery are critical for HIV-1 infection of all cells.Molecular Cell 06/2001; 7(5):1025-35. · 14.18 Impact Factor -
Article: HIV-1 sequence variation: drift, shift, and attenuation.
Cell 03/2001; 104(4):469-72. · 32.40 Impact Factor -
Article: An in vitro rapid-turnover assay for human immunodeficiency virus type 1 replication selects for cell-to-cell spread of virus.
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ABSTRACT: We have developed a rapid-turnover culture system where the life span of a human immunodeficiency virus type 1-infected cell is controlled by periodic addition of a cytotoxic agent, mitomycin C. These mitomycin C-exposed cells are cocultured with a constant number of uninfected cells as new targets for the virus. Passage of the virus-infected cells under these conditions led to the emergence of a viral variant that was able to replicate efficiently in this culture system. After biologic and molecular cloning, we were able to identify a single frameshift mutation in the vpu open reading frame that was sufficient for growth of the mutant virus in the rapid-turnover assay. This virus variant spread more efficiently by cell-to-cell transfer than the parental virus did. Electron micrographs of cells infected with the delta vpu virus revealed a large number of mature viral capsids attached to the plasma membrane. The presence of these mature virus particles on the cell surface led to enhanced fusion and formation of giant syncytia with uninfected cells. Enhanced cell-to-cell transfer of the delta vpu virus provides an explanation for the survival of this mutant virus in the rapid-turnover culture system. The in vitro rapid-turnover culture system is a good representation of the in vivo turnover kinetics of infected cells and their continual replacement by host lymphopoietic mechanisms.Journal of Virology 01/2001; 74(23):10882-91. · 5.40 Impact Factor -
Article: A competition model for viral inhibition of host cell proliferation.
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ABSTRACT: Some viruses encode proteins that promote cell proliferation while others, such as the human immunodeficiency virus (HIV), encode proteins that prevent cell division. It has been hypothesized that the selective advantage determining which strategy evolves depends on the ability of the virus to induce a cellular environment which maximizes both virus production and cell life span. In HIV, the protein that causes cell cycle arrest is Vpr. In this paper, we develop a mathematical model, based on difference equations, to study the competition between two genotypes of HIV - one that encodes this protein (Vpr+) and one that does not (Vpr-). In particular, we are interested in parameters that could be different between the in vitro condition, where the Vpr- genotype dominates, and the in vivo condition, where the Vpr+ genotype dominates. Our model indicates that the infected cell death-rate, the viral half-life, and the dynamics of the target cell population all effect the competition dynamics between the Vpr+ and Vpr- viral genotypes. Perturbing any of these parameters from the in vitro estimates while holding the others fixed has no affect on the competition outcome, i. e., the Vpr- genotype dominates. Perturbing the infected cell death-rate and the target cell source causes a switch in competitive outcome, although not necessarily at values, which represent the in vivo condition. Adding a perturbation in the viral half-life from in vitro to in vivo condition results in a switch of the competitive advantage from the Vpr- genotype to the Vpr+ genotype with parameters for all three mechanisms set to estimated in vivo values.Mathematical Biosciences 08/2000; 166(1):69-84. · 1.54 Impact Factor
