Viruses are always striving to outwit their host, and staying one step ahead is proving difficult in our fight against HIV-1. The expression of inhibitors, known as restriction factors, by humans and nonhuman primates provides an innate mechanism that confers resistance to infection with various retroviruses. However, it seems that HIV-1 can hijack a host protein to counteract the inhibition of virus replication mediated by these factors. Reporting in Nature Medicine, Towers et al. show that the interaction between HIV-1 capsid protein (CA) and the host cell protein cyclophilin A (CYPA) modulates the sensitivity of HIV-1 to host restriction factors.

The CYPA binding site in CA is positioned close to residues that are involved in recognition by restriction factors. So, the authors investigated how the interaction between CA and CYPA influences the sensitivity of HIV-1 to restriction factors. Disruption of the CYPA–CA interaction either by mutating the CYPA binding site in HIV-1 CA or by treating the target cells with cyclosporin A (CsA), which effectively competes for the binding of CYPA, had different effects on HIV-1 infectivity depending on the species of the target cell. In human cells, inhibition of the CYPA–CA interaction reduced the infectivity of HIV-1, as HIV-1 became sensitive to the restriction factor REF1. By contrast, efficient infection of owl monkey (OMK) cells occurred when the CYPA–CA interaction was prevented, indicating that this binding event is required for restriction by OMK cells.

Therefore, it seems that specific adaptation of HIV-1 in human cells, but not unnatural hosts, has allowed HIV-1 to avoid recognition by restriction factors and override innate antiviral safety measures.