12th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 22-25, 2005

Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 35

Jean-Marc Jacqué and M Stevenson
Univ of Massachusetts Med Sch, Worcester, USA

BACKGROUND: One of the most striking differences in the replication characteristics of lentiviruses (e.g., HIV-1) and onco-retroviruses (e.g., MLV) regards the differential ability to infect non-dividing cells. While HIV-1 infects non-dividing cells, such as primary macrophages or dendritic cells, MLV infects only cells in mitosis. The prevailing view is that the nuclear envelope acts as a barrier to MLV infection while viruses like HIV have evolved in mechanism to traverse it.

METHODS: We now have evidence that HIV-1 infection is restricted to non-dividing cells and have identified a novel block in mitotic cells. When cells are arrested in mitosis, the ability of HIV-1 to integrate into the host genome is markedly impaired. By subcellular fractionation, the block exists after HIV-1 accesses the nucleus but before integration, suggesting that a component of the nuclear envelope itself might be required for HIV-1 infection. Therefore, we suveyed components of the inner nuclear envelope by RNAi to identify factors necessary for viral infection.

RESULTS: By modulating proteins of the nuclear lamina, we have identified host cell nuclear proteins that are important for HIV to establish integration. Interactions between these proteins with the pre-integration complexes lead to proper integration of the HIV-1 genome into the host’s genomic DNA and subsequently to a productive infection. When these proteins are silenced by RNA interference, the viral cDNA retains the ability to localize to the nucleus but is unable to integrate and is unable to replicate. Our data unveil the existence of a “nuclear orientation” step in which the incoming viral cDNA must engage inner nuclear envelope proteins in order to position itself appropriately prior to interacting with the chromatin.

CONCLUSIONS: A better understanding of these critical steps in HIV infection will permit the design new therapeutic approaches for intervention of HIV-1 replication.

050222
35

Copyright © 2005 - Foundation for Retrovirology and Human Health. Reproduction of this abstract (other than one copy for personal reference) must be cleared through the Foundation for Retrovirology and Human Health. Licensed (AIDSLINE) from National Library of Medicine.