Human APOBEC3G‐mediated hypermutation is associated with antiretroviral therapy failure in HIV‐1 subtype C‐infected individuals

Neogi, Ujjwal; Shet, Anita; Sahoo, Pravat Nalini; Bontell, Irene; Banerjea, Akhil C.; Sönnerborg, Anders

doi:10.7448/ias.16.1.18472

Cited by 25 publications

(24 citation statements)

References 31 publications

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“…Similar data has been found using in vitro substrates for A3A that also deaminate at 5'TTC [119]. Accordingly, there is evidence that 5'TC modifying A3 enzymes may contribute more than A3G to HIV-1 evolution in the form of immune escape or drug resistance, rather than inducing HIV-1 inactivation [79,118,[120][121][122][123][124].…”

Section: Deamination-dependent Restriction Of Hiv By Apobec3fsupporting

confidence: 72%

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

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Apolipoprotein B mRNA-editing enzyme-catalytic, polypeptide-like 3 (APOBEC3) enzymes are a family of single-stranded (ss)DNA cytosine deaminases that serve as a host restriction factors for retrotransposons and viruses that contain a ssDNA intermediate. While the APOBEC3 family was originally expanded to restrict endogenous retroelements, the majority of these targets are now inactivated and the family has been found to act on different targets, such as viral ssDNA as a mechanism of viral defense. Some of the family members also catalyze "offtarget" deaminations in human ssDNA and have been implicated in somatic mutagenesis that can lead to cancer.My PhD thesis research investigated the biochemical mechanisms underlying both the benefits and the risks of the A3 family of enzymes. The central hypothesis of this work is that A3 enzymes have evolved distinct biochemical mechanisms to deaminate ssDNA that differentiate A3 restriction of retroelements and retroviruses from A3-induced somatic mutagenesis.Therefore, we investigated the biochemical mechanisms the A3 enzymes utilize during restriction of Human Immunodeficiency Virus (HIV) in both deamination-dependent and deaminationindependent modes, as well as the unique mechanisms employed during mutation of genomic DNA. There are seven APOBEC3 members (A-H, excluding E) and of these, four members (A3D, A3F, A3G, A3H) have been identified to restrict HIV replication in CD4 T+ cells, and currently three members (A3A, A3B and A3H haplotype I) have been implicated in somatic mutagenesis.The APOBEC3 enzymes that restrict HIV replication function optimally in the absence of the HIV viral infectivity factor (Vif). Vif targets APOBEC3 for degradation via the proteasome in HIV infected cells. For APOBEC3s that are able to fortuitously escape Vif mediated degradation and become encapsidated, the enzymes can deaminate cytosines to form uracils in viral (-)DNA. Replication of (-)DNA to (+)DNA causes HIV-1 reverse transcriptase to incorporate adenines opposite uracils which creates C/G→T/A transition mutations. While restriction of HIV most commonly occurs through this deamination-dependent mechanism, APOBEC3s have also been identified to interfere with HIV reverse transcriptase processes in a deamination-independent manner, although this mechanism is secondary to the deaminationdependent mode. In order to restrict retroelements and viruses such as HIV, the A3 enzymes iii require an efficient processive ssDNA scanning mechanism that allows them to search for, and locate cytosines on ssDNA in the finite amount of time the substrate is available during formation of the double-stranded DNA provirus. To understand if this requirement was lost in A3 enzymes unable to restrict HIV, we studied A3C. Human A3C is not able to restrict HIV, in comparison to the more active gorilla and chimpanzee A3C orthologs that can restrict HIV, however an explanation for this difference was lacking. A polymorphism, S188I, in human A3C, which is found in less than 3% of the global population lead...

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Section: Deamination-dependent Restriction Of Hiv By Apobec3fsupporting

confidence: 72%

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

2018

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“…The host factors APOBEC3F and APOBEC3G induce G-to-A substitutions in reverse-transcribed nascent retroviral DNA (70). G-to-A hypermutations play an important role in the evolution of antiretroviral drug resistance (71,72) and could be associated with ART failure (73). The extent of G-to-A hypermutations is not associated with levels of HIV-1 RNA (74), although hypermutations are frequent in viremic controllers (75).…”

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confidence: 99%

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

et al. 2015

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HIV genotyping is a critical tool for antiviral drug resistance testing that has revolutionized HIV care and advanced HIVrelated research. Routine antiretroviral (ARV) drug resistance testing is useful in choosing an optimal treatment regimen and monitoring its efficiency in clinical practice (1-12). HIV genotyping has been used successfully in research on HIV transmission clusters and HIV transmission dynamics (13-35).Initial broadly used ARV regimens included combinations of nucleoside reverse transcriptase (RT) inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). To monitor the emergence of drug resistance mutations associated with NRTIs and NNRTIs, HIV genotyping targeted viral sequences spanning an approximately 1,000-to 1,300-bp region of the HIV-1 genome encoding viral protease and partial RT, using viral RNA as a template for amplification. While the RNA-based approach works well in antiretroviral therapy (ART)-naive individuals, it is less successful if levels of viral replication are low, such as in individuals on ART. The sequence length of traditional RNAbased HIV genotyping for drug resistance is relatively short and does not cover the HIV-1 region encoding viral integrase or the viral envelope, hindering analysis of drug resistance mutations associated with integrase strand transfer inhibitors or entry inhibitors. The global scale up of ARV treatment and successful introduction of integrase strand transfer inhibitors and entry inhibitors into clinical trials and clinical practice necessitate modification of traditional methods of HIV genotyping.Two commercial genotyping assays, ViroSeq HIV-1 from Abbott Molecular and TruGene HIV-1 from Siemens Molecular Diagnostics, have been widely used for analysis of HIV-1-associated drug resistance. Both genotyping kits were extensively tested and validated (36)(37)(38)(39)(40)(41)(42)(43)(44)(45). While the ViroSeq HIV-1 kit is still on the market, Siemens discontinued selling and supporting the TruGene HIV-1 kit in 2014. The ViroSeq HIV-1 kit covers the entire protease-coding region and the RT region encoding the first 320 amino acids. The TruGene HIV-1 sequences span the protease (amino acids 4 to 99)-and RT (amino acids 40 to 240)-coding regions. The CDC supplies WHO-designated and CDC-supported President's Emergency Plan for AIDS Relief (PEPFAR) Genotyping Laboratories with the ATCC HIV-1 Drug Resistance Genotyping kit (46) for drug resistance testing. Many experienced genotyping laboratories have developed their own in-house amplification and sequencing protocols (11,(47)(48)(49)(50)(51)(52)(53)(54)(55)(56), including identification of minor viral variants that are normally missed by commercial genotyping kits (57-61). All of these approaches generally include smaller and more restricted regions for testing HIV-1 drug resistance.Recently, the protocol developed by Gall et al. (62)

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“…In the oral TDF arm, 1 of 30 participants showed M184I at a low level (2.5 %), a mutation that is not selected by TDF. This mutation was detected as a minor variant in the placebo arm of Partners PrEP, FEM-PrEP, and iPrEx participants, possibly maintained at low levels by APOBEC3G-induced G-to-A hypermutation (Neogi et al 2013). …”

Section: Genotypic Phenotypic and Minor Variant Drug Resistance In mentioning

confidence: 95%

HIV-1 Drug Resistance in Preexposure Prophylaxis Trials

Liegler¹,

Grant²

2014

Handbook of Antimicrobial Resistance

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When used with other proven strategies for prevention of HIV-1 acquisition, oral and topical preexposure prophylaxis (PrEP) has been shown to be effective in multiple randomized, placebocontrolled clinical trials throughout the world. Preexposure prophylaxis trials have included over 20,000 men and women at risk for HIV infection through sexual or intravenous exposure. A consistent finding is that drug exposure is essential for PrEP efficacy. In PrEP users with breakthrough infection, selection of drug-resistant virus is a possible outcome, presenting a unique sequence of events and outcomes compared with therapeutic use of antiretroviral drugs. Study findings have indicated that drug resistance selected by PrEP occurs rarely, except in cases where PrEP is initiated in very early infection, prior to seroconversion, and detectable only with nucleic acid tests. In this review, we discuss the factors associated with PrEP which may contribute to drug resistance and summarize the frequency and characteristics of HIV-1 drug resistance reported to date from global clinical trials. A theoretical framework of the causes and consequences of drug resistance in PrEP is considered as a basis of the real-life outcomes and challenges in implementing PrEP.

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Human APOBEC3G‐mediated hypermutation is associated with antiretroviral therapy failure in HIV‐1 subtype C‐infected individuals

Cited by 25 publications

References 31 publications

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Biochemical Basis of APOBEC3 Deoxycytidine Deaminase Activity on Diverse DNA Substrates

Long-Range HIV Genotyping Using Viral RNA and Proviral DNA for Analysis of HIV Drug Resistance and HIV Clustering

HIV-1 Drug Resistance in Preexposure Prophylaxis Trials

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