14th Conference on Retroviruses and Opportunistic Infections Los Angeles, California - February 25-28, 2007

Conf Retrovir Opportunistic Infect 2007 Feb 25-28;14: (abstract no. 48)

Vineet KewalRamani¹, Z Ambrose¹, T Martin¹, K Lee¹, N Vandegraaff², A Mulky¹, J Coffin³, A Engelman², S Hughes¹, and D Unutmaz^4
1HIV Drug Resistance Prgm, NCI, Frederick, MD, US; ²Dana-Farber Cancer Inst, Boston, MA, US; ³Tufts Univ, Boston, MA, US; and ⁴New York Univ Sch of Med, NY, US

BACKGROUND: Among the different genera of retroviruses, lentiviruses, such as HIV-1, are particularly efficient in the infection of nondividing cells and parasitize such cells during in vivo replication. Replication in nondividing cells necessitates that lentiviruses exploit strategies that facilitate transfer of the viral nucleic acid across an enduring nuclear membrane to access the host cell chromatin. We have discovered an antiviral protein, truncated CPSF6, that opposes the nuclear entry of HIV-1, but does not impair infection by murine leukemia viruses. Selection for HIV-1 resistance to truncated CPSF6 identified an N74D mutation in CA. Screening of other residues in CA identified E45A and Q63A/Q67A to confer resistance to truncated CPSF6 in HeLa cells. Because these different CA mutant viruses evaded a block to nuclear entry in dividing cells, we evaluated the infectivity of such viruses using nondividing cell targets, and observed 2 different phenotypes. E45A and Q63A/Q67A HIV-1 were markedly reduced in their ability to infect growth arrested HeLa cells but only slightly diminished in their ability to infect macrophages. By contrast, N74D HIV-1 was not impaired in the infection of growth arrested HeLa cells, but could not replicate in macrophages in which its genome appears to be rapidly degraded.

CONCLUSIONS: We hypothesize that the different mutations influence CA dissociation from the HIV-1 reverse transcription complex (RTC), and that truncated CPSF6 interferes with cellular factors that aid in this dissociation. In such a model, nuclear entry by HIV-1 is regulated via CA dissociation from the RTC, which itself is dependent on cell factors targeted by truncated CPSF6.

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2007-02-25
48

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