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Journal of Virology, September 1998, p. 7032-7039, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Regions of Human Immunodeficiency Virus Type 1 nef Required for Function In Vivo

Grace M. Aldrovandi,1 Lianying Gao,2 Gregory Bristol,2 and Jerome A. Zack3,*

University of Alabama at Birmingham AIDS Center, Birmingham, Alabama 35294,1 and Division of Hematology-Oncology, Department of Medicine,2 and Department of Microbiology and Molecular Genetics,3 University of California---Los Angeles School of Medicine and University of California Los Angeles AIDS Institute, Los Angeles, California 90095-1678

Received 9 September 1997/Accepted 19 May 1998

In vivo studies in monkeys and humans have indicated that immunodeficiency viruses with Nef deleted are nonpathogenic in immunocompetent hosts, and this has motivated a search for live attenuated vaccine candidates. However, the mechanisms of action of Nef remain elusive. To define the regions of human immunodeficiency virus type 1 (HIV-1) Nef which mediate in vivo pathogenicity, a series of mutated isogenic viruses were inoculated into human thymic implants in SCID-hu mice. Mutation of several regions, including the myristoylation site at the second glycine and a region encompassing amino acids 41 through 49 of Nef, profoundly affected pathogenicity. Surprisingly, mutations of prolines in either of the two distant PXXP SH3 binding domains did not affect pathogenicity, indicating that these regions are not required for Nef activity in developing T-lineage cells. These data suggest that some functions of Nef described in vitro may not be relevant for in vivo pathogenicity.

* Corresponding author. Mailing address: Department of Microbiology and Molecular Genetics, UCLA School of Medicine and UCLA AIDS Institute, 10833 Le Conte Ave., Los Angeles, CA 90095-1678. Phone: (310) 794-7765. Fax: (310) 825-6192. E-mail: jzack{at}ucla.edu.

Journal of Virology, September 1998, p. 7032-7039, Vol. 72, No. 9
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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