Most retroviral vectors used for gene therapy are derived from C-type viruses, which cannot infect quiescent cells. Lentiviruses such as HIV-1, on the other hand, can infect quiescent cells, but concerns have been raised about their safety for human gene therapy. In this issue, Parveen et al. (see p. 623) describe how they developed an engineered retroviral vector that has the safety features of spleen necrosis virus (SNV), a C-type retroviral vector, and that can efficiently infect quiescent cells. Previous studies have suggested that HIV-1 can infect nondividing cells with the help of a nuclear localization sequence (NLS) located in the matrix protein. The matrix proteins of SNV and HIV-1 are structurally similar, so the researchers tried mutating residues in the region of the SNV matrix protein analogous to the NLS in HIV-1. They found that by altering just two amino acids, they could produce a C-type retroviral vector capable of infecting growth-arrested human T lymphocytes and quiescent primary monocyte-derived macrophages. In addition to its implications for gene therapy, the results support the notion that the NLS is sufficient to mediate the ability of HIV-1 to infect nondividing cells.