Sakuma, Ryuta

ABSTRACT Dominant, constitutively expressed antiretroviral factors, including TRIM5α and APOBEC3 proteins, are distinguished from the conventional innate immune systems and are classified as intrinsic immunity factors. Here, we demonstrate that interferon alpha (IFN-α) treatment upregulates TRIM5α mRNA in rhesus monkey cells, which correlates with the enhanced TRIM5α-mediated pre- and postintegration blocks of human immunodeficiency virus replication. In human cells, IFN-α increases the levels of TRIM5α mRNA, resulting in enhanced antiviral activity against N-tropic murine leukemia virus infection. These observations indicate that the TRIM5α-mediated antiviral effects can be orchestrated by the conventional innate immune response. It is conceivable that TRIM5α plays an essential role in controlling both the initial retroviral exposure and the subsequent viral dissemination in vivo.

ABSTRACT Murine primary cells are poorly permissive to human immunodeficiency virus type 1 (HIV-1) vector infection. Retroviral infectivity is influenced by dominant inhibitors such as TRIM5α. Sensitivity to TRIM5α is altered by interactions between cyclophilin A and the HIV-1 capsid. Here we demonstrate that competitive inhibitors of cyclophilins, cyclosporine or the related Debio-025, stimulate HIV-1 vector transduction of primary murine cells, including bone marrow and macrophages, up to 20-fold. Unexpectedly, the infectivity of an HIV-1 mutant or a simian lentivirus that does not recruit cyclophilin A is also stimulated by these drugs. We propose that cyclosporine and related compounds will be useful tools for experimental infection of murine primary cells. It is possible that HIV-1 infection of murine cells is inhibited by dominant factors related to immunophilins.