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Journal of Virology, July 2007, p. 7099-7110, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00272-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 cDNAs Produced in the Presence of APOBEC3G Exhibit Defects in Plus-Strand DNA Transfer and Integration{triangledown} ,{dagger}

Jean L. Mbisa,1 Rebekah Barr,1 James A. Thomas,2 Nick Vandegraaff,3 Irene J. Dorweiler,4 Evguenia S. Svarovskaia,1,{ddagger} William L. Brown,4,5 Louis M. Mansky,4 Robert J. Gorelick,2 Reuben S. Harris,4,5 Alan Engelman,3 and Vinay K. Pathak1*

HIV Drug Resistance Program,1 AIDS Vaccine Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, Maryland 21702-1201,2 Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute and the Division of AIDS, Harvard Medical School, Boston, Massachusetts 02115,3 University of Minnesota, Departments of Diagnostic and Biological Sciences and Microbiology and Institute for Molecular Virology, Minneapolis, Minnesota 55455,4 University of Minnesota, Department of Biochemistry, Molecular Biology and Biophysics, Arnold and Mabel Beckman Center for Transposon Research, Minneapolis, Minnesota 554555

Received 8 February 2007/ Accepted 5 April 2007

Encapsidation of host restriction factor APOBEC3G (A3G) into vif-deficient human immunodeficiency virus type 1 (HIV-1) blocks virus replication at least partly by C-to-U deamination of viral minus-strand DNA, resulting in G-to-A hypermutation. A3G may also inhibit HIV-1 replication by reducing viral DNA synthesis and inducing viral DNA degradation. To gain further insight into the mechanisms of viral inhibition, we examined the metabolism of A3G-exposed viral DNA. We observed that an overall 35-fold decrease in viral infectivity was accompanied by a five- to sevenfold reduction in viral DNA synthesis. Wild-type A3G induced an additional fivefold decrease in the amount of viral DNA that was integrated into the host cell genome and similarly reduced the efficiency with which HIV-1 preintegration complexes (PICs) integrated into a target DNA in vitro. The A3G C-terminal catalytic domain was required for both of these antiviral activities. Southern blotting analysis of PICs showed that A3G reduced the efficiency and specificity of primer tRNA processing and removal, resulting in viral DNA ends that are inefficient substrates for integration and plus-strand DNA transfer. However, the decrease in plus-strand DNA transfer did not account for all of the observed decrease in viral DNA synthesis associated with A3G. These novel observations suggest that HIV-1 cDNA produced in the presence of A3G exhibits defects in primer tRNA processing, plus-strand DNA transfer, and integration.

* Corresponding author. Mailing address: HIV Drug Resistance Program, National Cancer Institute-Frederick, P.O. Box B, Bldg. 535, Rm. 334, Frederick, MD 21702-1201. Phone: (301) 846-1710. Fax: (301) 846-6013. E-mail: vpathak{at}ncifcrf.gov

{triangledown} Published ahead of print on 11 April 2007.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org.

{ddagger} Present address: Gilead Sciences, Inc., Durham, NC 27707-3458.

Journal of Virology, July 2007, p. 7099-7110, Vol. 81, No. 13
0022-538X/07/$08.00+0     doi:10.1128/JVI.00272-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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