Role and Mechanism of Action of the APOBEC3 Family of Antiretroviral Resistance Factors

Abstract

Metazoan organisms are subject to invasion by a wide range of microbial pathogens and have, as a result, evolved a range of defensive measures. While scientific attention historically has focused on adaptive immune responses, such as antibodies and cytotoxic T cells, it has of late become increasingly apparent that innate immunity also plays a key role in shielding animals from infection (62). Unlike adaptive immunity, innate immunity acts immediately and thus can prevent an infection from getting started. Innate immunity may be particularly effective at shielding animals from infection by opportunistic or zoonotic pathogens. However, because innate immune responses are largely invariant, microorganisms that are common pathogens of a given animal species will frequently have evolved mechanisms that confer resistance to relevant innate immune responses in that species. Indeed, comparative analyses of a host innate immune response and the microbial countermeasures to that response can provide key insights into the biological mechanisms underlying these antagonistic processes.A wide range of innate immune responses have been identified; many of these rely on the recognition of a "pathogenassociated molecular pattern" (PAMP) that is characteristic of a given type of pathogen (62). In this paper, I will review our current understanding of one protein family, the apolipoprotein B mRNA editing enzyme catalytic polypeptide 3 (APO BEC3) proteins, which can confer innate immunity to a wide range of exogenous retroviruses. Moreover, individual APO BEC3 family members can also block the replication of hepatitis B virus, a distant relative of retroviruses, and inhibit the replication of retrotransposons, endogenous transposable elements related to retroviruses that can disrupt the integrity of host cell genomes. APOBEC3 PROTEIN FAMILYThe genomes of humans and other primates encode at least five, and possibly up to seven, APOBEC3 proteins, all of which are encoded by a single gene cluster on chromosome 22 (20). This gene cluster appears to be unique to primates, as the genomes of several other mammalian species, such as mice, cats, and cows, encode only a single APOBEC3 protein (31,36). The fact that the single APOBEC3 gene found in these other vertebrates is at the syntenic chromosomal location relative to the primate APOBEC3 gene cluster (66) indicates that the primate APOBEC3 gene family appeared relatively recently in vertebrate evolution due to gene duplication. This finding, together with the observation that the rate of nonsynonymous nucleotide substitutions has been significantly higher than the rate of synonymous substitutions during the evolution of several members of the APOBEC3 gene family, suggests that primate APOBEC3 genes have been under significant selective pressure (47a, 75). As discussed below, it seems possible that the evolutionary pressure for amplification and diversification of the primate APOBEC3 genes arose from the appearance of viral mechanisms that are able to neutralize the APOBEC3-mediated inhi...

Murine leukemia virus glycosylated Gag blocks apolipoprotein B editing complex 3 and cytosolic sensor access to the reverse transcription complex

“…Some retroviruses, such as HIV, simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV), encode Vif proteins that bind APOBEC3 proteins and target them for degradation in virus-producing cells. Additionally, the Bet protein of feline foamy viruses inhibits APOBEC3 by as yet undetermined means (16) and human T-cell leukemia virus I prevents packaging of APOBEC3G, although not APOBEC3A, 3B, or 3H (47,48). However, APOBEC3 inhibits infection by a number of viruses that encode no apparent vif-or bet-like genes, and how these viruses overcome restriction is not known.…”

“…APOBEC3 genes belong to a family of genes that encode DNA and RNA editing enzymes (16). The human genome contains seven genes, whereas mice have only one gene (17).…”

The human RBPome: From genes and proteins to human disease

“…The low conservation class ( Figure 3D) comprised of genes having orthologs in less than 50% of the species. Genes in this group included DCD-an antimicrobial peptide coding gene, member of the APOBEC family which are specific to primates and mammals [54]. Furthermore, nLRP11 -a member of the Nod-like receptor protein family was observed to be present only in mammals [55].…”

Cellular inhibitors of long interspersed element 1 and Alu retrotransposition

“…The ability of human APOBEC3G (A3G) to function as an innate inhibitor of exogenous retroviruses was first noted during studies analyzing the HIV type 1 (HIV-1) Vif protein (6,13). These experiments revealed that A3G is a potent inhibitor of Vif-deficient, but not wild-type, HIV-1 replication.…”

“…Humans are subject to infection by a limited number of exogenous retroviruses and contain few, if any, biologically active LTR retrotransposons, although a small number of structurally similar endogenous retroviruses may remain viable (5,6). However, humans contain Ϸ100 intact LINE-1 elements (7,8), and de novo LINE-1 and short interspersed element retrotransposition events occur in Ϸ10% of human genomes per generation (9,10).…”