HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy

Blanch-Lombarte, Oscar; Santos, JR; Peña, Ruth; Jiménez-Moyano, Esther; Clotet, Bonaventura; Paredes, Roger; Prado, Julia G.

doi:10.1093/jac/dkaa228

Cited by 9 publications

(18 citation statements)

References 50 publications

(72 reference statements)

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“…These mutations have also been documented by previous studies as being associated with PI/r regimen 10,12,14 . Moreover, class I mutations (e.g., L449F and Y484P) occurred principally in combination with several major PI/r resistance mutations, suggesting that they emerge after a prolonged PI/r exposure, when the virus has already accumulated a large number of PI/r resistance mutations.…”

Section: Discussionsupporting

confidence: 71%

“…Also, Gag mutation D480E which is recognized as a PI-exposure associated mutation 17 signi cantly correlated with two major PI/r resistance mutations (I54V and V82A). In the other hand, given that some studies have shown that only Gag mutations are capable of inducing resistance to darunavir 12 , the role of the novel mutation I479G which did not signi cantly correlate with any major or accessory PI/r resistance mutation deserve to be investigated.…”

Section: Discussionmentioning

confidence: 99%

“…As mechanism of resistance may differ between B and non-B variants, studies on non-B variants are limited. Some adherent patients failing treatment on PI/r-based ART do not harbor any major protease mutations, thus suggesting the detrimental effects of closer genes like Gag on the resulting poor treatment response 12 . This calls for further investigation on Gag genes for a successful scaling-up of PI/r-based ART in RLS like Cameroon.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Evaluation of C-terminal p7 (NC)-p6 Gag genetic variants among HIV-1 non-B subtypes in a subset of Cameroonian patients

Této

Nka

Fokam

et al. 2021

Preprint

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Response to ritonavir-boosted-protease inhibitors (PI/r)-based regimen is associated with some Gag mutations among HIV-1 B-clade. There is limited data on Gag variants and their covariation with mutations in protease among HIV-1 non-B-clades at PI/r-based treatment failure. Thus, we characterized Gag variants present in isolates from HIV-1 infected individuals treated to a PI/r-regimen (n=143) and compared them to those obtained from individuals not treated to PI/r (ART-naïve [n=101] or RTI-treated [n=118]). The most frequent HIV-1 subtypes were CRF02_AG (54.69%), A (13.53%), D (6.35%) and G (4.69%). Eighteen Gag variants (distributed in three groups) showed a significantly higher prevalence in PI/r-treated isolates compared to ART-naïve (p<0.05): Group 1 (prevalence <1% in drug-naïve): L449F, D480N, L483Q, Y484P, T487V; group 2 (prevalence 1%-5% in drug-naïve): S462L, I479G, I479K, D480E; group 3 (prevalence ≥5% in drug-naïve): P453L, E460A, R464G, S465F, V467E, Q474P, I479R, E482G, T487A. Five Gag variants (L449F, P453L, D480E, S465F, Y484P) positively correlated (Phi ≥0.2, p<0.05) with protease-resistance mutations. At PI/r-failure, no significant difference was observed between patients with and without these associated Gag variants in term of viremia or CD4 count. This analysis suggests that some Gag variants are significantly associated with an increased frequency at PI/r failure among HIV-1 non-B clades.

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Section: Discussionsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Evaluation of C-terminal p7 (NC)-p6 Gag genetic variants among HIV-1 non-B subtypes in a subset of Cameroonian patients

Této

Nka

Fokam

et al. 2021

Preprint

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“…In cases of drug-resistant mutants, they do not always acquire mutations in the sites targeted by drugs. For example, the development of resistance against a protease inhibitor (PI) has been reported to result from the emergence of mutations in the Gag or Envelope (Env) region but not in the Pol-protease region [ 28 , 29 , 30 , 31 , 32 ]. Even in Vif-null HIV-1 clones, adaptive clones that emerged during an adaptation experiment developed A3G resistance without Vif expression [ 33 , 34 ], although there is a report that a Vif-null HIV-1 clone failed to do so [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process

Koma

Doi

Takemoto

et al. 2021

Viruses

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HIV-1 Vif plays an essential role in viral replication by antagonizing anti-viral cellular restriction factors, a family of APOBEC3 proteins. We have previously shown that naturally-occurring single-nucleotide mutations in the SA1D2prox region, which surrounds the splicing acceptor 1 and splicing donor 2 sites of the HIV-1 genome, dramatically alter the Vif expression level, resulting in variants with low or excessive Vif expression. In this study, we investigated how these HIV-1 variants with poor replication ability adapt and evolve under the pressure of APOBEC3 proteins. Adapted clones obtained through adaptation experiments exhibited an altered replication ability and Vif expression level compared to each parental clone. While various mutations were present throughout the viral genome, all replication-competent adapted clones with altered Vif expression levels were found to bear them within SA1D2prox, without exception. Indeed, the mutations identified within SA1D2prox were responsible for changes in the Vif expression levels and altered the splicing pattern. Moreover, for samples collected from HIV-1-infected patients, we showed that the nucleotide sequences of SA1D2prox can be chronologically changed and concomitantly affect the Vif expression levels. Taken together, these results demonstrated the importance of the SA1D2prox nucleotide sequence for modulating the Vif expression level during HIV-1 replication and adaptation.

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“…By contrast, PI resistance mutations following failure of current boosted PI treatments are uncommon in LMIC 13 , a situation that differs for less potent drugs used in the early PI era 5 . A number of studies have indicated that less well characterised mutations accumulating in the gag gene during PI failure might also impact PI susceptibility [14][15][16][17][18][19][20] , though common pathways have been difficult to discern, likely reflecting plasticity to drug escape.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 evolutionary dynamics under non-suppressive antiretroviral therapy

Kemp

Charles

Derache

et al. 2021

Preprint

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Background: Viral population dynamics in long term viraemic antiretroviral therapy (ART) treated individuals have not been well characterised. Prolonged virologic failure on 2nd-line protease inhibitor (PI) based ART without emergence of major protease mutations is well recognised, providing an opportunity to study within-host evolution. Methods: Using next-generation Illumina short read sequencing and in silico haplotype reconstruction we analysed whole genome sequences from longitudinal plasma samples of eight chronically infected HIV-1 individuals failing 2nd-line regimens from the ANRS 12249 TasP trial, in the absence of high frequency major PI resistance mutations. Plasma drug levels were measured by HPLC. Three participants were selective for in-depth variant and haplotype analyses, each with five or more timepoints spanning at least 16 months. Results: During PI failure synonymous mutations were around twice as frequent as non-synonymous mutations across participants. Prior to or during exposure to PI, we observed several polymorphic amino acids in gag (e.g. T81A, T375N) which are have also been previously associated with exposure to protease inhibitor exposure. Although overall SNP frequency at abundance above 2% appeared stable across time in each individual, divergence from the consensus baseline sequence did increase over time. Non-synonymous changes were enriched in known polymorphic regions such as env whereas synonymous changes were more often observed to fluctuate in the conserved pol gene. Phylogenetic analyses of whole genome viral haplotypes demonstrated two common features: Firstly, evidence for selective sweeps following therapy switches or large changes in plasma drug concentrations, with hitchhiking of synonymous and non-synonymous mutations. Secondly, we observed competition between multiple viral haplotypes that intermingled phylogenetically alongside soft selective sweeps. The diversity of viral populations was maintained between successive timepoints with ongoing viremia, particularly in env. Changes in haplotype dominance were often distinct from the dynamics of drug resistance mutations in reverse transcriptase (RT), indicating the presence of softer selective sweeps and/or recombination. Conclusions: Large fluctuations in variant frequencies with diversification occur during apparently "stable" viremia on non-suppressive ART. Reconstructed haplotypes provided further evidence for sweeps during periods of partial adherence, and competition between haplotypes during periods of low drug exposure. Drug resistance mutations in RT can be used as markers of viral populations in the reservoir and we found evidence for loss of linkage disequilibrium for drug resistance mutations, indicative of recombination. These data imply that even years of exposure to PIs, within the context of large stable populations displaying ongoing selective competition, may not precipitate emergence of major PI resistance mutations, indicating significant fitness costs for such mutations. Ongoing viral diversification within reservoirs may compromise the goal of sustained viral suppression.

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HIV-1 Gag mutations alone are sufficient to reduce darunavir susceptibility during virological failure to boosted PI therapy

Cited by 9 publications

References 50 publications

Evaluation of C-terminal p7 (NC)-p6 Gag genetic variants among HIV-1 non-B subtypes in a subset of Cameroonian patients

Evaluation of C-terminal p7 (NC)-p6 Gag genetic variants among HIV-1 non-B subtypes in a subset of Cameroonian patients

The Expression Level of HIV-1 Vif Is Optimized by Nucleotide Changes in the Genomic SA1D2prox Region during the Viral Adaptation Process

HIV-1 evolutionary dynamics under non-suppressive antiretroviral therapy

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