Murine leukemia virus p12 functions include hitchhiking into the nucleus

When a retrovirus infects a new host cell, its genomic RNA is copied into double-stranded (ds) DNA by the reverse transcriptase enzyme present in the incoming virus particle. This DNA synthesis takes place in the cytoplasm of the cell; the DNA must then make its way into the nucleus before it can be inserted into the chromosomal DNA by the integrase enzyme (which is also carried in the incoming virus). In PNAS, Schneider et al. (1) elegantly dissect some of the complexities of nuclear entry of Moloney murine leukemia virus (MuLV) DNA. Retroviruses are divided into two subfamilies (i.e., orthoretroviruses and spumaretroviruses). There are six orthoretrovirus genera: alpha-, beta-, gamma-, delta-, epsilon-, and lentiviruses. MuLV is a prototypical gammaretrovirus and has served as the basis for a major class of gene-therapy vectors now under development. A significant difference between gammaretroviruses and many other retroviruses, including the lentivirus HIV-1, is that gammaretroviruses can only infect proliferating cells (2), whereas HIV-1 can infect nondividing cells (3). This ability is a crucial element in HIV-1 biology. When the dsDNA copy of the retroviral genome enters the nucleus, it is part of the “pre-integration complex” (PIC), which also contains proteins from the virus particle, including integrase (IN) and capsid (CA) (the major structural protein of the mature virus particle), in addition to proteins from the host cell. HIV-1 CA interacts, directly or indirectly, with nuclear import machinery (4); this interaction enables the HIV-1 PIC to enter the interphase nucleus, leading to the successful infection of a nondividing cell. Unlike HIV-1, gammaretroviral PICs cannot cross the nuclear membrane. This is why gammaretroviral infections require dividing cells, in which the nuclear membrane has broken down. The work by Schneider et al. (1) sheds light on how MuLV ensures that, once the nuclear membrane has reformed at …