Abstract
The human APOBEC3 (A3) family (A, B, C, DE, F, G, and H) comprises host defense factors that potently inhibit the replication of diverse retroviruses, retrotransposons, and the other viral pathogens. HIV-1 has a counterstrategy that includes expressing the Vif protein to abrogate A3 antiviral function. Without Vif, A3 proteins, particularly APOBEC3G (A3G) and APOBEC3F (A3F), inhibit HIV-1 replication by blocking reverse transcription and/or integration and hypermutating nascent viral cDNA. The molecular mechanisms of this antiviral activity have been primarily attributed to two biochemical characteristics common to A3 proteins: catalyzing cytidine deamination in single-stranded DNA (ssDNA) and a nucleic acid-binding capability that is specific to ssDNA or ssRNA. Recent advances suggest that unique property of A3G dimer/oligomer formations, is also important for the modification of antiviral activity. In this review article we summarize how A3 proteins, particularly A3G, inhibit viral replication based on the biochemical and structural characteristics of the A3G protein.
Highlights
Productive infections of primary human lymphocytes, monocytes, and certain T-cell lines by HIV-1 require a virally encoded gene product, Vif
In early work on Vif, vif-deficient virions produced in non-permissive cells were found to be significantly impaired in their ability to complete reverse transcription (Sova and Volsky, 1993; von Schwedler et al, 1993), and they were 100- to 1000-fold less infectious than wild type (WT) virions (Fisher et al, 1987; Strebel et al, 1987; Fouchier et al, 1996)
What is the fundamental mechanism(s) of A3G antiviral activity that explains the observation by von Schwedler et al (1993), that the reverse transcription of vif-deficient HIV-1 is impaired when produced from A3G-expressing “non-permissive” cells?
Summary
Productive infections of primary human lymphocytes, monocytes, and certain T-cell lines by HIV-1 require a virally encoded gene product, Vif (originally named “Sor” or “A”; Fisher et al, 1987; Strebel et al, 1987). After A3G was suggested as the key restriction factor against vif-deficient HIV-1, it was proposed that A3G-mediated deamination might be a lethal trigger, eventually leading to the degradation of reversetranscribed viral DNA through a base-excision pathway and/or the reduced replication of progeny viruses by introducing premature stop codons and/or amino acid changes (Cullen, 2003; Goff, 2003; Harris et al, 2003a,b; KewalRamani and Coffin, 2003).
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