ChemInform Abstract: Emerging Complexities of APOBEC3G Action on Immunity and Viral Fitness During HIV Infection and Treatment

Immunology and Infectious Diseases Program, Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, Newfoundland, Canada.
Retrovirology (Impact Factor: 4.19). 04/2012; 9(31):35. DOI: 10.1186/1742-4690-9-35
Source: PubMed


The enzyme APOBEC3G (A3G) mutates the human immunodeficiency virus (HIV) genome by converting deoxycytidine (dC) to deoxyuridine (dU) on minus strand viral DNA during reverse transcription. A3G restricts viral propagation by degrading or incapacitating the coding ability of the HIV genome. Thus, this enzyme has been perceived as an innate immune barrier to viral replication whilst adaptive immunity responses escalate to effective levels. The discovery of A3G less than a decade ago led to the promise of new anti-viral therapies based on manipulation of its cellular expression and/or activity. The rationale for therapeutic approaches has been solidified by demonstration of the effectiveness of A3G in diminishing viral replication in cell culture systems of HIV infection, reports of its mutational footprint in virions from patients, and recognition of its unusually robust enzymatic potential in biochemical studies in vitro. Despite its effectiveness in various experimental systems, numerous recent studies have shown that the ability of A3G to combat HIV in the physiological setting is severely limited. In fact, it has become apparent that its mutational activity may actually enhance viral fitness by accelerating HIV evolution towards the evasion of both anti-viral drugs and the immune system. This body of work suggests that the role of A3G in HIV infection is more complex than heretofore appreciated and supports the hypothesis that HIV has evolved to exploit the action of this host factor. Here we present an overview of recent data that bring to light historical overestimation of A3G's standing as a strictly anti-viral agent. We discuss the limitations of experimental systems used to assess its activities as well as caveats in data interpretation.

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    • "Mutations in CTL epitopes of HIV favor immune evasion by reducing CTL recognition and activation [36]–[40]. Although A3G/F are intrinsic anti-viral barriers that function early in infection, once the CTL response escalates to effective levels, the limited action of A3G/F may actually aid HIV by mutating its CTL epitopes towards immune evasion [19], [41]. In support of this possibility, the most highly mutating sites in HIV genomes mediating CTL escape are somewhat enriched in A3G hotspots [41]. "
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    ABSTRACT: Due to constitutive expression in cells targeted by human immunodeficiency virus (HIV), and immediate mode of viral restriction upon HIV entry into the host cell, APOBEC3G (A3G) and APOBEC3F (A3F) have been considered primarily as agents of innate immunity. Recent bioinformatic and mouse model studies hint at the possibility that mutation of the HIV genome by these enzymes may also affect adaptive immunity but whether this occurs in HIV-infected individuals has not been examined. We evaluated whether APOBEC-mediated mutations within common HIV CD8+ T cell epitopes can potentially enhance or diminish activation of HIV-specific CD8+ T cells from infected individuals. We compared ex vivo activation of CD8+ T lymphocytes from HIV-infected individuals by wild type HIV peptide epitopes and synthetic variants bearing simulated A3G/F-induced mutations by measuring interferon-γ (IFN-γ) production. We found that A3G/F-induced mutations consistently diminished HIV-specific CD8+ T cell responses against the common epitopes we tested. If this reflects a significant trend in vivo, then adaptation by HIV to enrich sequences that are favored for mutation by A3G/F (A3G/F hotspots) in portions of its genome that encode immunogenic CD8+ T cell epitopes would favor CTL escape. Indeed, we found the most frequently mutated A3G motif (CCC) is enriched up to 6-fold within viral genomic sequences encoding immunodominant CD8+ T cell epitopes in Gag, Pol and Nef. Within each gene, A3G/F hotspots are more abundant in sequences encoding epitopes that are commonly recognized due to their HLA restriction. Thus, in our system, mutations of the HIV genome, mimicking A3G/F activity, appeared to abrogate or severely reduce CTL recognition. We suggest that the physiological significance of this potential effect in facilitating CTL escape is echoed in the adaptation of the HIV genome to enrich A3G/F hotspots in sequences encoding CTL epitopes that are more immunogenic at the population level.
    Full-text · Article · Apr 2014 · PLoS ONE
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    • "New approaches to ARV development include targeting innate immune responses shown to be effective in HIV suppression. Some of the targets include ‘APOBEC 3G' that interferes with viral DNA synthesis, ‘Tetherin' that blocks viral release and TRIMα that destabilizes the HIV capsid and interferes with reverse transcription.93,94,95,96,97 Another candidate target is ‘LEDGF/p75', an integrase enzyme cofactor, whose antagonists are being studied for their ability to suppress HIV replication.98 "
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    • "Cellular restriction factors are another host defense against HIV infection. These include, but are not limited to, TRIM5α [18,19], APOBEC3G [20,21], SAMHD1 [22,23] and miRNAs [24,25]. "
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    ABSTRACT: Host cell microRNAs (miRNAs) have been shown to regulate the expression of both cellular and viral RNAs, in particular impacting both Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV). To investigate the role of miRNAs in regulating replication of the simian immunodeficiency virus (SIV) in macrophage lineage cells, we used primary macrophages to study targeting of SIV RNA by miRNAs. We examined whether specific host miRNAs directly target SIV RNA early in infection and might be induced via type I interferon pathways. miRNA target prediction programs identified miRNA binding sites within SIV RNA. Predicted binding sites for miRs-29a, -29b, -9 and -146a were identified in the SIV Nef/U3 and R regions, and all four miRNAs decreased virus production and viral RNA expression in primary macrophages. To determine whether levels of these miRNAs were affected by SIV infection, IFNbeta or TNFalpha treatments, miRNA RT-qPCR assays measured miRNA levels after infection or treatment of macrophages. SIV RNA levels as well as virus production was downregulated by direct targeting of the SIV Nef/U3 and R regions by four miRNAs. miRs-29a, -29b, -9 and -146a were induced in primary macrophages after SIV infection. Each of these miRNAs was regulated by innate immune signaling through TNFalpha and/or the type I IFN, IFNbeta. The effects on miRNAs caused by HIV/SIV infection are illustrated by changes in their cellular expression throughout the course of disease, and in different patient populations. Our data demonstrate that levels of primary transcripts and mature miRs-29a, -29b, -9 and -146a are modulated by SIV infection. We show that the SIV 3[prime] UTR contains functional miRNA response elements (MREs) for all four miRNAs. Notably, these miRNAs regulate virus production and viral RNA levels in macrophages, the primary cells infected in the CNS that drive inflammation leading to HIV-associated neurocognitive disorders. This report may aid in identification miRNAs that target viral RNAs and HIV/SIV specifically, as well as in identification of miRNAs that may be targets of new therapies to treat HIV.
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