APOBEC3G-Mediated G-to-A Hypermutation of the HIV-1 Genome: The Missing Link in Antiviral Molecular Mechanisms

Abstract

APOBEC3G (A3G) is a member of the cellular polynucleotide cytidine deaminases, which catalyze the deamination of cytosine (dC) to uracil (dU) in single-stranded DNA. These enzymes potently inhibit the replication of a variety of retroviruses and retrotransposons, including HIV-1. A3G is incorporated into vif-deficient HIV-1 virions and targets viral reverse transcripts, particularly minus-stranded DNA products, in newly infected cells. It is well established that the enzymatic activity of A3G is closely correlated with the potential to greatly inhibit HIV-1 replication in the absence of Vif. However, the details of the underlying molecular mechanisms are not fully understood. One potential mechanism of A3G antiviral activity is that the A3G-dependent deamination may trigger degradation of the dU-containing reverse transcripts by cellular uracil DNA glycosylases (UDGs). More recently, another mechanism has been suggested, in which the virion-incorporated A3G generates lethal levels of the G-to-A hypermutation in the viral DNA genome, thus potentially driving the viruses into “error catastrophe” mode. In this mini review article, we summarize the deaminase-dependent and deaminase-independent molecular mechanisms of A3G and discuss how A3G-mediated deamination is linked to antiviral mechanisms.

Impact of Antiretroviral Therapy Duration on HIV-1 Infection of T Cells within Anatomic Sites

“…HIV-1 replication is characterized by rapid and highly error-prone reverse transcription, which lacks proofreading capacity and causes genetic defects in viral genomes (15,(36)(37)(38)(39)(40). Also, an antiviral mechanism called G-to-A hypermutation renders in-frame stop codons and produces replication-deficient HIV-1 DNA during reverse transcription (15,41,42). These genetic defects have been identified in memory T cells during therapy (43)(44)(45).…”

TRIM41-Mediated Ubiquitination of Nucleoprotein Limits Vesicular Stomatitis Virus Infection

“…The "pre-existed" expression of these host factors guarantees a more rapid response and a direct inhibition of viral infection [10,25]. For example, the cytidine deaminase, apolipoprotein editing complex 3 G (APOBEC3G), introduces transversion mutations into the HIV genome, thereby impeding HIV infection [26]. It is well established for how innate immunity responds to VSV infection; however, the intrinsic immune response to VSV is still elusive.…”

Insight into the dynamics of APOBEC3G protein in complexes with DNA assessed by high speed AFM

“…6 It was shown that A3G efficiently binds ssDNA and restricts retroviruses with deamination-dependent and deamination-independent restriction pathways. 1,[7][8][9][10][11][12] A3G has two domains with Z-dependent motifs: the C terminal domain (CTD), which is catalytically active, and the N-terminal domain (NTD), which is responsible for ssDNA binding. 13 Both domains contribute to the anti-retroviral activity during the viral replication cycle.…”