Novel TRIM5 Isoforms Expressed by Macaca nemestrina

The human immunodeficiency virus (HIV) pandemic is the result of cross-species transmissions of simian immunodeficiency virus (SIV) from non-human primates to humans (28). The recent discovery of human T-cell leukemia virus types 3 and 4 suggests that cross-species transmission of retroviruses is not an infrequent occurrence (33). However, to establish a productive infection in a new species, it is necessary for retroviruses to evade host-specific restriction factors. A broad range of antiretroviral host restriction factors has been identified in mammalian species. The best-described primate host restriction factors are APOBEC3F/G and TRIM5α. APOBEC3F/G are cytidine deaminases which exert a late block to retroviral replication, inhibiting the virus in target cells rather than producer cells (29), whereas TRIM5α exerts a dominant block to infection immediately after viral entry into the cell through the inhibition of reverse transcription (30). TRIM5α is a member of the tripartite motif family of proteins, also called RBCC proteins, because of the presence of a RING domain (C3HC4 type), one or two B boxes, and a coiled-coil region in an ordered arrangement from N terminus to C terminus (23). Six isoforms of TRIM5 have been identified in mammals (26). These proteins have been shown to form homo- and heteromultimers, although only homomultimers of TRIM5α have been shown to restrict lentiviruses (3, 8, 15, 30, 37). The antiretroviral activity of TRIM5α is mediated through an interaction between the viral capsid and the B30.2(SPRY) domain (12, 20, 21, 31). The B30.2(SPRY) domain is the primary determinant of species-specific differences in the breadth and potency of TRIM5α antiretroviral activity. For instance, changing the arginine found in human TRIM5α at position 332 to the proline residue found in rhesus TRIM5α enables human TRIM5α to restrict HIV type 1 (HIV-1) nearly as efficiently as rhesus TRIM5α. Additionally, the ability of African green monkeys to restrict SIVmac has been mapped to a 37-amino-acid insertion in the B30.2(SPRY) domain (16, 36). Efficient binding of capsid-nucleocapsid complexes by TRIM5α requires coiled-coil-mediated trimerization, presumably to increase the avidity between the B30.2(SPRY) domain and capsid (10). Disruptions to the RING and B-box domains can also inhibit the antiviral activity of TRIM5α through currently undefined mechanisms (15, 22, 27). Our laboratory has shown that Macaca nemestrina animals are susceptible to infection with a primary HIV-2 isolate, HIV-2/EHO (14, 25). M. nemestrina macaques have also been reported to be susceptible to some HIV-1 isolates (1, 4-7, 19) although this idea remains controversial. These observations led us to examine the TRIM5 gene of M. nemestrina for species-specific differences that may explain the apparent susceptibility of this macaque species to infection with HIV.