HIV and other lentiviruses can productively infect nondividing cells, whereas most other retroviruses, such as murine leukemia virus, require cell division for efficient infection. However, the determinants for this phenotype have been controversial. Here, we show that HIV-1 capsid (CA) is involved in facilitating HIV infection of nondividing cells because amino acid changes on CA severely disrupt the cell-cycle independence of HIV. One mutant in the N-terminal domain of CA in particular has lost the cell-cycle independence in all cells tested, including primary macrophages. The defect in this mutant appears to be at a stage past nuclear entry. We also find that the loss of cell-cycle independence can be cell-type specific, which suggests that a cellular factor affects the ability of HIV to infect nondividing cells. Our data suggest that CA is directly involved at some step in the viral life cycle that is important for infection of nondividing cells.
HIV and related viruses are unusual among retroviruses in their ability to replicate independently of cell-cycle progression of target cells. However, the determinants of this phenotype have been controversial. Here, we identified mutations on the surface of the capsid (CA) protein that reduce the ability of HIV to infect nondividing cells. These mutations also confer cell-cycle dependency on HIV, even in dividing cells. Interestingly, some CA mutants lose cell-cycle independence only in certain cell types. Thus, these findings suggest that a cellular factor targeting CA regulates HIV-1 infection in nondividing cells. Surprisingly, these mutations do not appear to affect nuclear localization of viral genomes, which points to a novel regulation of the cell-cycle independence of HIV by the CA protein.