The HIV‐1 Vif protein suppresses the inhibition of viral replication caused by the human antiretroviral factor APOBEC3G. As a result, HIV‐1 mutants that do not express the Vif protein are replication incompetent in ‘nonpermissive’ cells, such as primary T cells and the T‐cell line CEM, that express APOBEC3G. In contrast, Vif‐defective HIV‐1 replicates effectively in ‘permissive’ cell lines, such as a derivative of CEM termed CEM‐SS, that do not express APOBEC3G. Here, we show that a second human protein, APOBEC3F, is also specifically packaged into HIV‐1 virions and inhibits their infectivity. APOBEC3F binds the HIV‐1 Vif protein specifically and Vif suppresses both the inhibition of virus infectivity caused by APOBEC3F and virion incorporation of APOBEC3F. Surprisingly, APOBEC3F and APOBEC3G are extensively coexpressed in nonpermissive human cells, including primary lymphocytes and the cell line CEM, where they form heterodimers. In contrast, both genes are quiescent in the permissive CEM derivative CEM‐SS. Together, these data argue that HIV‐1 Vif has evolved to suppress at least two distinct but related human antiretroviral DNA‐editing enzymes.

Long interspersed element (LINE) 1 retrotransposons are major genomic parasites that represent Ϸ17% of the human genome. The LINE-1 ORF2 protein is also responsible for the mobility of Alu elements, which constitute a further Ϸ11% of genomic DNA. Representative members of each element class remain mobile, and deleterious retrotransposition events can induce spontaneous genetic diseases. Here, we demonstrate that APOBEC3A and APOBEC3B, two members of the APOBEC3 family of human innate antiretroviral resistance factors, can enter the nucleus, where LINE-1 and Alu reverse transcription occurs, and specifically inhibit both LINE-1 and Alu retrotransposition. These data suggest that the APOBEC3 protein family may have evolved, at least in part, to defend the integrity of the human genome against endogenous retrotransposons.APOBEC3 protein ͉ mutagenesis ͉ retrotransposon ͉ genome stability ͉ intrinsic immunity