Target cell APOBEC3C can induce limited G-to-A mutation in HIV-1

• Published in: PLoS pathogens 2007-10, Vol.3 (10), p.1477-1485
• Main Authors: Bourara, Khaoula, Liegler, Teri J, Grant, Robert M
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adenine; AIDS; Blotting, Western; Cell Line; Clone Cells; Cloning; Cytidine Deaminase - genetics; Cytidine Deaminase - metabolism; Deoxyribonucleic acid; DNA; DNA Mutational Analysis; DNA, Viral - metabolism; Drug resistance; Drug Resistance, Viral - genetics; Editing; Evolutionary Biology; Gene mutations; Gene Products, vif; Genes, gag; Genetic aspects; Guanine; Health aspects; HIV infection; HIV Infections - genetics; HIV-1 - genetics; Humans; Infections; Infectious Diseases; Molecular Biology; Molecular weight; Monkeys & apes; Mutation; Physiological aspects; Point Mutation; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Small Interfering; Transfection; Virology; Virus Replication - physiology; Viruses
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.0030153

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.