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

Conf Retrovir Opportunistic Infect 2005 Feb 22-25;12:abstract no. 34

Matthew Stremlau, M Perron, B Song, S Welikala, and J Sodroski
Dana-Farber Cancer Inst, Boston, MA, USA

BACKGROUND: HIV-1 can enter the cells of all Old World primates, yet the epidemic is confined to humans and apes. Recently, a genetic screen identified the cytoplasmic body component TRIM5α as a major post-entry restriction factor in Old World monkey cells. TRIM5α is a member of a large, but poorly characterized family of proteins defined by a tripartite motif consisting of RING, B-box 2, and coiled-coil domains. TRIM5α is the largest of the TRIM5 isoforms and contains a C-terminal B30.2(SPRY) domain. Rhesus monkey TRIM5α more potently blocks HIV-1 infection than human TRIM5α. Analysis of species-specific variation in TRIM5α has identified 3 variable regions (v1, v2, and v3) within the B30.2(SPRY) domain. The TRIM5α proteins of Old World primates exhibit expansion, duplication, and residue variation specifically in the v1 region.

METHODS: We constructed a panel of rhesus and human chimeric TRIM5α proteins. Stable cell lines expressing these chimeric proteins were tested for susceptibility to infection with HIV-1-GFP viruses.

RESULTS: By analyzing the chimeric TRIM5α proteins we show that the major determinant of anti-HIV-1 potency is the B30.2(SPRY) domain. Replacement of 3 amino acids in the N-terminus of the human TRIM5α B30.2 v1 region resulted in a molecule that restricted HIV-1 nearly as efficiently as wild type rhesus TRIM5α. Surprisingly, a single amino acid change in this region of human TRIM5α allowed potent restriction of SIV_mac, a phenotype not observed for either wild type human or rhesus TRIM5α.

CONCLUSIONS: Chimeric TRIM5α proteins that are more than 98% identical to the human protein can potently block HIV-1. These proteins may have therapeutic utility, and also provide important mechanistic insights into TRIM5α antiviral activity.

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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.