APOBEC3F Properties and Hypermutation Preferences Indicate Activity against HIV-1 In Vivo

Abstract

APOBEC3G (CEM15 ) deaminates cytosine to uracil in nascent retroviral cDNA. The potency of this cellular defense is evidenced by a dramatic reduction in viral infectivity and the occurrence of high frequencies of retroviral genomic-strand G --> A transition mutations. The overwhelming dinucleotide hypermutation preference of APOBEC3G acting upon a variety of model retroviral substrates is 5'-GG --> -AG. However, a distinct 5'-GA --> -AA bias, which is difficult to attribute to APOBEC3G alone, prevails in HIV-1 sequences derived from infected individuals (e.g., ). Here, we show that APOBEC3F is also a potent retroviral restrictor but that its activity, unlike that of APOBEC3G, is partially resistant to HIV-1 Vif and results in a clear 5'-GA --> -AA retroviral hypermutation preference. This bias is also apparent in a bacterial mutation assay, suggesting that it is an intrinsic APOBEC3F property. Moreover, APOBEC3F and APOBEC3G appear to be coordinately expressed in a wide range of human tissues and are independently able to inhibit retroviral infection. Thus, APOBEC3F and APOBEC3G are likely to function alongside one another in the provision of an innate immune defense, with APOBEC3F functioning as the major contributor to HIV-1 hypermutation in vivo.

Interferon-inducible expression of APOBEC3 editing enzymes in human hepatocytes and inhibition of hepatitis B virus replication

“…The initial report of the APO-BEC3 gene cluster failed to detect expression of A3G or A3B in human liver by Northern blotting; however, two subsequent studies demonstrated co-expression of A3G and A3F in many organs, including the human liver, by Northern blotting or RT-PCR. 20,42,43 Our study confirms the expression of A3G and A3F in normal human liver and proves the hepatic expression of A3B mRNA. Thus, the concluding statement of Rösler et al 33 that a role of APOBEC3 cytidine deaminases in the HBV life cycle is speculative because expression of cytidine deaminases in untransformed liver has not been shown has to be amended.…”

“…[17][18][19] In addition, the editing enzymes APOBEC3F (A3F) and APOBEC3B (A3B) inhibit HIV-1, and A3B and APOBEC3C (A3C) restrict simian immunodeficiency virus replication by cytidine deamination of the viral minus strand cDNA, and A3B and to a lesser extent also A3F are resistant to HIV Vif-induced proteosomal degradation. [20][21][22][23] Recent evidence suggests that some of the HIV restriction exerted by A3G may be independent of its cytidine deaminase activity. [24][25][26] G-to-A hypermutated HBV genomes have been detected in the plasma of HBV-infected patients, suggesting that APOBEC3 editing enzymes have edited the minus strand cDNA during HBV replication.…”

APOBEC3F and APOBEC3G mRNA Levels Do Not Correlate with Human Immunodeficiency Virus Type 1 Plasma Viremia or CD4 + T-Cell Count

“…However, hA3F and hA3G mRNA abundances revealed a positive, linear relationship (Pearson's correlation coefficient of 0.283; P ϭ 0.003) (Fig. 2), in agreement with previous studies in which hA3F and hA3G showed similar patterns of expression in tissues and were postulated to be coordinately regulated (1,12,26). It should be noted that our cross-sectional survey was not aimed at identifying long-term nonprogressors and, therefore, did not include sufficient numbers to allow valid statistical evaluations of this subgroup.…”

“…In the absence of the human immunodeficiency virus type 1 (HIV-1) accessory protein Vif, hA3F and hA3G are incorporated into virions and induce G-to-A hypermutations in the viral genome (1,8,12,14,27,29,30). Vif counteracts hA3F and hA3G by preventing their encapsidation within virions and by inducing their proteasomal degradation (4,11,13,16,17,24,25,28).…”

A putative antiviral role of plant cytidine deaminases

“…HIV-1 hypermutated genomes show mutational hot spots as well, which are due to preference of A3G and A3F for deamination of the third C in 5’-CCC (negative-strand) and 5’-GGC, respectively 51, 52 . The context of the C complementary to G181 (5’-GGC) differs from what has been described for APOBEC3, suggesting that if At CDAs had context preference, it would be different from the one described for A3G.…”