Cytidine Deamination of Retroviral DNA by Diverse APOBEC Proteins

Abstract

The human cytidine deaminase APOBEC3G edits both nascent human immunodeficiency virus (HIV) and murine leukemia virus (MLV) reverse transcripts, resulting in loss of infectivity. The HIV Vif protein is able to protect both viruses from this innate restriction to infection. Here, we demonstrate that a number of other APOBEC family members from both humans and rodents can mediate anti-HIV effects, through cytidine deamination. Three of these, rat APOBEC1, mouse APOBEC3, and human APOBEC3B, are able to inhibit HIV infectivity even in the presence of Vif. Like APOBEC3G, human APOBEC3F preferentially restricts vif-deficient virus. Indeed, the mutation spectra and expression profile found for APOBEC3F indicate that this enzyme, together with APOBEC3G, accounts for the G to A hypermutation of proviruses described in HIV-infected individuals. Surprisingly, although MLV infectivity is acutely reduced by APOBEC3G, no other family member tested here had this effect. It is especially interesting that although both rodent APOBECs markedly diminish wild-type HIV infectivity, MLV is resistant to these proteins. This implies that MLV may have evolved to avoid deamination by mouse APOBEC3. Overall, our findings show that although APOBEC family members are highly related, they exhibit significantly distinct antiviral characteristics that may provide new insights into host-pathogen interactions.

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.…”

“…APOBEC3F (hA3F) and APOBEC3G (hA3G) are members of a family of related cytidine deaminases shown to have antiretroviral activity in vitro (1,8,9,11,14,23,29). 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).…”

“…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).…”

Reconstructing immune phylogeny: new perspectives

“…So, the appearance of a class-switch reaction was dependent on the evolution of switch-region sequences. AID-like and uracil-DNA glycosylase (UNG)-like proteins, which are involved in these processes, had ancient origins, co-evolving with innate immune antiviral defences [49][50][51] .…”

“…So, the appearance of a class-switch reaction was dependent on the evolution of switch-region sequences. AID-like and uracil-DNA glycosylase (UNG)-like proteins, which are involved in these processes, had ancient origins, co-evolving with innate immune antiviral defences [49][50][51] .Over time, V-gene duplication and germline substitutions, which were focused in COMPLEMENTARITY-DETERMINING REGION 1 (CDR1) and CDR2, coupled with combinatorial joining, imparted a considerable selective advantage in terms of deriving receptor diversity. Somatic hypermutation of immunoglobulin genes, which is a central feature of BCR maturation, occurs in the earliest extant jawed vertebrates -the cartilaginous fish 52,53 -and might be an accentuation of a genome-wide process 54,55 .…”