Abstract
The evolutionary success of primate lentiviruses reflects their high capacity to mutate and adapt to new host species, immune responses within individual hosts, and, in recent years, antiviral drugs. APOBEC3G (A3G) and APOBEC3F (A3F) are host cell DNA-editing enzymes that induce extensive HIV-1 mutation that severely attenuates viral replication. The HIV-1 virion infectivity factor (Vif), expressed in vivo, counteracts the antiviral activity of A3G and A3F by inducing their degradation. Other APOBECs may contribute more to viral diversity by inducing less extensive mutations allowing viral replication to persist. Here we show that in APOBEC3C (A3C)-expressing cells infected with the patient-derived HIV-1 molecular clones 210WW, 210WM, 210MW, and 210MM, and the lab-adapted molecular clone LAI, viral G-to-A mutations were detected in the presence of Vif expression. Mutations occurred primarily in the GA context and were relatively infrequent, thereby allowing for spreading infection. The mutations were absent in cells lacking A3C but were induced after transient expression of A3C in the infected target cell. Inhibiting endogenous A3C by RNA interference in Magi cells prevented the viral mutations. Thus, A3C is necessary and sufficient for G-to-A mutations in some HIV-1 strains. A3C-induced mutations occur at levels that allow replication to persist and may therefore contribute to viral diversity. Developing drugs that inhibit A3C may be a novel strategy for delaying viral escape from immune or antiretroviral inhibition.
Highlights
The evolutionary success of primate lentiviruses is evident from their prevalence in Old-World primates and their capacity to spread to new host species, frequently leading to the emergence of zoonotic disease [1,2]
We showed that a human protein, called APOBEC3C (A3C), could induce certain mutations in some HIV-1 strains, including those derived from a patient who had developed rapid drug resistance
We conclude that A3C is necessary and sufficient to induce signature mutations in HIV-1
Summary
The evolutionary success of primate lentiviruses is evident from their prevalence in Old-World primates and their capacity to spread to new host species, frequently leading to the emergence of zoonotic disease [1,2]. Establishing persistent infection in individual hosts requires high mutation rates and rapid and extensive viral adaptation, which allows the virus to escape from humoral and cell-mediated immune responses [3,4]. Rapid viral adaptation produces drug resistance that limits the effectiveness of therapy in many patients. An important mechanism of HIV genetic variation is Gto-A mutation during reverse transcription [5,6]. Such mutations can be mediated by a family of DNA-editing enzymes with a strong preference for specific dinucleotide contexts [7,8,9,10]. G-to-A mutations have been detected in at least 43% of HIV-1-infected patients, indicating that such mutations occur in a setting of persistent replication [17]
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