The study investigates the role of CEM15 (APOBEC3G) in HIV-1 DNA hypermutation. CEM15, an endogenous inhibitor of HIV-1 replication, is shown to be a cytidine deaminase that induces G to A hypermutation in newly synthesized viral DNA. This effect is counteracted by the HIV-1 virion infectivity factor (Vif). The authors demonstrate that CEM15-mediated hypermutation can occur in both non-permissive and permissive cells, and that it preferentially occurs in GpA or GpG dinucleotide contexts. The hypermutation is not dependent on dNTP pool imbalances but is dependent on CEM15's cytidine deaminase activity. The study also shows that CEM15 can induce non-lethal hypermutation in wild-type viruses during long-term culture, contributing to genetic variation in primate lentiviral populations. The findings suggest that CEM15 may act as a viral defense mechanism, potentially leading to lethal hypermutation or instability of viral reverse transcripts.The study investigates the role of CEM15 (APOBEC3G) in HIV-1 DNA hypermutation. CEM15, an endogenous inhibitor of HIV-1 replication, is shown to be a cytidine deaminase that induces G to A hypermutation in newly synthesized viral DNA. This effect is counteracted by the HIV-1 virion infectivity factor (Vif). The authors demonstrate that CEM15-mediated hypermutation can occur in both non-permissive and permissive cells, and that it preferentially occurs in GpA or GpG dinucleotide contexts. The hypermutation is not dependent on dNTP pool imbalances but is dependent on CEM15's cytidine deaminase activity. The study also shows that CEM15 can induce non-lethal hypermutation in wild-type viruses during long-term culture, contributing to genetic variation in primate lentiviral populations. The findings suggest that CEM15 may act as a viral defense mechanism, potentially leading to lethal hypermutation or instability of viral reverse transcripts.