Cellular Restriction Targeting Viral Capsids Perturbs Human Immunodeficiency Virus Type 1 Infection of Nondividing Cells

The ability of human immunodeficiency virus (HIV) to infect nondividing cells is a fundamental property by which HIV replicates in critical target cells, such as macrophages and resting CD4(+) T cells. Recent studies have revealed that the capsid (CA) protein is a dominant factor that determines retrovirus infectivity in nondividing cells, and several mutations in HIV type 1 (HIV-1) CA abrogate the ability of HIV-1 to infect nondividing cells. We present evidence for a connection between cellular restriction against viral capsids and the resistance of nondividing cells to retrovirus infection. TRIM proteins that are able to target incoming viral capsids restrict HIV-1 more potently in nondividing cells than in dividing cells, thus rendering HIV-1 infection dependent on cell division. Moreover, cyclophilin A, another cellular protein that binds to HIV-1 CA, regulates HIV-1 infection of nondividing cells. Together, these data demonstrate the importance of capsid-binding cellular proteins in the control of the cell cycle independence of HIV-1. We propose that cellular restrictions to retroviral infections are themselves cell cycle dependent.