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Journal of Virology, March 2005, p. 3139-3145, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.3139-3145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Species-Specific Variation in the B30.2(SPRY) Domain of TRIM5{alpha} Determines the Potency of Human Immunodeficiency Virus Restriction

Matthew Stremlau,1 Michel Perron,1 Sohanya Welikala,1 and Joseph Sodroski1,2*

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Department of Pathology, Division of AIDS, Harvard Medical School,1 Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts2

Received 14 July 2004/ Accepted 13 October 2004

Retroviruses encounter dominant postentry restrictions in cells of particular species. Human immunodeficiency virus type 1 (HIV-1) is blocked in the cells of Old World monkeys by TRIM5{alpha}, a tripartite motif (TRIM) protein composed of RING, B-box 2, coiled-coil, and B30.2(SPRY) domains. Rhesus monkey TRIM5{alpha} (TRIM5{alpha}rh) more potently blocks HIV-1 infection than human TRIM5{alpha} (TRIM5{alpha}hu). Here, by studying chimeric TRIM5{alpha} proteins, we demonstrate that the major determinant of anti-HIV-1 potency is the B30.2(SPRY) domain. Analysis of species-specific variation in TRIM5{alpha} has identified three variable regions (v1, v2, and v3) within the B30.2 domain. The TRIM5{alpha} proteins of Old World primates exhibit expansion, duplication, and residue variation specifically in the v1 region. Replacement of three amino acids in the N terminus of the TRIM5{alpha}hu B30.2 v1 region with the corresponding TRIM5{alpha}rh residues resulted in a TRIM5{alpha} molecule that restricted HIV-1 nearly as efficiently as wild-type TRIM5{alpha}rh. Surprisingly, a single-amino-acid change in this region of TRIM5{alpha}hu allowed potent restriction of simian immunodeficiency virus, a phenotype not observed for either wild-type TRIM5{alpha}hu or TRIM5{alpha}rh. Some of the chimeric TRIM5{alpha} proteins that are >98% identical to the human protein yet mediate a strong restriction of HIV-1 infection may have therapeutic utility. These observations implicate the v1 variable region of the B30.2(SPRY) domain in TRIM5{alpha}rh antiviral potency.

* Corresponding author. Mailing address: Dana-Farber Cancer Institute, 44 Binney St., JFB 824, Boston, MA 02115. Phone: (617) 632-3371. Fax: (671) 632-4338. E-mail: joseph_sodroski{at}dfci.harvard.edu.

Journal of Virology, March 2005, p. 3139-3145, Vol. 79, No. 5
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.5.3139-3145.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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