Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

With limited and low-genetic barrier drugs used for the prevention of mother-to-child transmission (PMTCT) of HIV in sub-Saharan Africa, vertically transmitted HIV-1 drug-resistance (HIVDR) is concerning and might prompt optimal pediatric strategies.The aim of this study was to ascertain HIVDR and viral-tropism in majority and minority populations among Cameroonian vertically infected children.A comparative analysis among 18 HIV-infected children (7 from PMTCT-exposed mothers and 11 from mothers without PMTCT-exposure) was performed. HIVDR and HIV-1 co-receptor usage was evaluated by analyzing sequences obtained by both Sanger sequencing and ultra-deep 454-pyrosequencing (UDPS), set at 1% threshold.Overall, median (interquartile range) age, viremia, and CD4 count were 6 (4–10) years, 5.5 (4.9–6.0) log10 copies/mL, and 526 (282–645) cells/mm3, respectively. All children had wild-type viruses through both Sanger sequencing and UDPS, except for 1 PMTCT-exposed infant harboring minority K103N (8.31%), born to a mother exposed to AZT+3TC+NVP. X4-tropic viruses were found in 5 of 15 (33.3%) children (including 2 cases detected only by UDPS). Rate of X4-tropic viruses was 0% (0/6) below 5 years (also as minority species), and became relatively high above 5 years (55.6% [5/9], P = .040. X4-tropic viruses were higher with CD4 ≤15% (4/9 [44.4%]) versus CD4 >15% (1/6 [16.7%], P = .580); similarly for CD4 ≤200 (3/4 [75%]) versus CD4 >200 (2/11 [18.2%] cells/mm3, P = .077.NGS has the ability of excluding NRTI- and NNRTI-mutations as minority species in all but 1 children, thus supporting the safe use of these drug-classes in those without such mutations, henceforth sparing ritonavir-boosted protease inhibitors or integrase inhibitors for the few remaining cases. In children under five years, X4-tropic variants would be rare, suggesting vertical-transmission with CCR5-tropic viruses and possible maraviroc usage at younger ages.

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“…A nested mid-PCR was then performed with the Fast Start HiFi PCR system (Roche Diagnostics, Mannheim, Germany) as previously described. [ 26 ]…”

Section: Methodsmentioning

confidence: 99%

“…Pooled purified PCR products were clonally amplified by emulsion PCR and pyro-sequenced on the 454 GS junior platform (Roche Applied Science, Mannheimer Germany) as previously described. [ 26 ] Phylogenetic analyses excluded any possible sample contamination (data not shown).…”

Section: Methodsmentioning

confidence: 99%

Next-generation sequencing provides an added value in determining drug resistance and viral tropism in Cameroonian HIV-1 vertically infected children

Fokam

Bellocchi

Armenia³

et al. 2018

Medicine

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“…HIV restriction factors can prevent viral budding, decrease nuclear accumulation of viral cDNAs, interfere with reverse transcription, and induce mutagenesis of proviral DNA [1, 2]. While viral evolution to continually evade host restriction occurs constantly through selected mutations resulting from reverse transcriptase (RT) error there may also be a contribution from a group of host restriction factors [12, 13, 14, 15, 16]. The APOBEC3 (A3) restriction factors of HIV can induce mutagenesis of proviral DNA by deaminating cytosine to form promutagenic uracil in (−) DNA when it is single stranded [1, 2, 17].…”

Section: Introductionmentioning

confidence: 99%

“…These data in combination with data demonstrating that during chronic HIV-1 infection Vif can acquire mutations that partially decrease its ability to induce A3 degradation suggest that HIV-1 can manipulate A3 activity like a mutational rheostat [44, 45, 68]. Evidence of this has come from studies that have assessed antiviral drug resistance, CTL epitopes, and co-receptor usage, some of which used less effective Vif variants isolated from HIV-1+ individuals [12, 15, 16, 68, 69, 70, 74, 75, 76, 77].…”

Section: Introductionmentioning

confidence: 99%

Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance

Mohammadzadeh

Love

Gibson

et al. 2019

Heliyon

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The APOBEC3 enzymes can induce mutagenesis of HIV-1 proviral DNA through the deamination of cytosine. HIV-1 overcomes this restriction through the viral protein Vif that induces APOBEC3 proteasomal degradation. Within this dynamic host-pathogen relationship, the APOBEC3 enzymes have been found to be beneficial, neutral, or detrimental to HIV-1 biology. Here, we assessed the ability of co-expressed APOBEC3F and APOBEC3G to induce HIV-1 resistance to antiviral drugs. We found that co-expression of APOBEC3F and APOBEC3G enabled partial resistance of APOBEC3F to Vif-mediated degradation with a corresponding increase in APOBEC3F-induced deaminations in the presence of Vif, in addition to APOBEC3G-induced deaminations. We recovered HIV-1 drug resistant variants resulting from APOBEC3-induced mutagenesis, but these variants were less able to replicate than drug resistant viruses derived from RT-induced mutations alone. The data support a model in which APOBEC3 enzymes cooperate to restrict HIV-1, promoting viral inactivation over evolution to drug resistance.

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“…Therefore, A3G is also presumably involved in the production of defective viruses in vivo (Pace et al, 2006; Armitage et al, 2012; Eyzaguirre et al, 2013; Krisko et al, 2013; Sato et al, 2014; Delviks-Frankenberry et al, 2016). However, the incomplete neutralization of A3 family proteins by Vif might result in sequence diversification in vivo (Simon et al, 2005; Kim et al, 2010, 2014; Sato et al, 2014; Alteri et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

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

Okada

Iwatani

2016

Front. Microbiol.

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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.

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Incomplete APOBEC3G/F Neutralization by HIV-1 Vif Mutants Facilitates the Genetic Evolution from CCR5 to CXCR4 Usage

Cited by 10 publications

References 70 publications

Next-generation sequencing provides an added value in determining drug resistance and viral tropism in Cameroonian HIV-1 vertically infected children

Next-generation sequencing provides an added value in determining drug resistance and viral tropism in Cameroonian HIV-1 vertically infected children

Role of co-expressed APOBEC3F and APOBEC3G in inducing HIV-1 drug resistance

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

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