The host factor α isoform of the tripartite motif 5 (TRIM5α) restricts human immunodeficiency virus type 1 (HIV-1) infection in certain non-human primate species. Restriction of HIV-1 is enhanced by binding of the viral capsid to cyclophilin A (CypA) in target cells, although CypA is not absolutely required for restriction in rhesus macaque cells. Simian immunodeficiency virus (SIV) is not restricted by rhesus macaque TRIM5α and its capsid does not bind to CypA. Here, the effect of lentiviral CypA dependence on restriction in different tissues was examined by engineering an HIV-1 capsid quadruple mutant (V86P/H87Q/I91V/M96I) lentiviral vector (HIVquad) that is CypA-independent. Whereas HIV-1 was restricted in rhesus macaque and owl monkey epithelial cells, infection with the HIVquad vector was efficient at high viral concentrations. In contrast, HIVquad was largely restricted in primary rhesus macaque CD34+ cells. Human epithelial and primary CD34+ cells were permissive for HIV-1, HIVquad and SIV, whereas transduction of human T cells by HIVquad or SIV was impaired. The restrictive human cells did not express increased levels of TRIM5α, and restriction was not relieved by abolishing CypA, consistent with HIVquad and SIV being CypA-independent. Pseudotyping of lentiviral vectors with the gibbon ape leukemia virus envelope altered their sensitivity to perturbations of the virus-CypA interaction compared to pseudotyping with vesicular stomatitis virus glycoproteins, suggesting that the viral entry pathway modulates restriction. Together, these studies reveal that an HIV-1 capsid quadruple mutant can partially overcome lentiviral restriction in non-human primate epithelial cells, but not in hematopoietic cells. Similarly, human cells vary in their permissiveness for CypA-independent lentiviruses, and suggest the presence of tissue-specific factor(s) that can inhibit lentiviral transduction independently of viral interaction with TRIM5α and CypA.
ASJC Scopus subject areas