Unknown

Dataset Information

0

Coevolved Multidrug-Resistant HIV-1 Protease and Reverse Transcriptase Influences Integrase Drug Susceptibility and Replication Fitness.


ABSTRACT: Integrase strand transfer inhibitors (InSTIs) are recommended agents in first-line combination antiretroviral therapy (cART). We examined the evolution of drug resistance mutations throughout HIV-1 pol and the effects on InSTI susceptibility and viral fitness. We performed single-genome sequencing of full-length HIV-1 pol in a highly treatment-experienced patient, and determined drug susceptibility of patient-derived HIV-1 genomes using a phenotypic assay encompassing full-length pol gene. We show the genetic linkage of multiple InSTI-resistant haplotypes containing major resistance mutations at Y143, Q148 and N155 to protease inhibitor (PI) and reverse transcriptase inhibitor (RTI) resistance mutations. Phenotypic analysis of viruses expressing patient-derived IN genes with eight different InSTI-resistant haplotypes alone or in combination with coevolved protease (PR) and RT genes exhibited similar levels of InSTI susceptibility, except for three haplotypes that showed up to 3-fold increases in InSTI susceptibility (p ≤ 0.032). The replicative fitness of most viruses expressing patient-derived IN only significantly decreased, ranging from 8% to 56% (p ≤ 0.01). Interestingly, the addition of coevolved PR + RT significantly increased the replicative fitness of some haplotypes by up to 73% (p ≤ 0.024). Coevolved PR + RT contributes to the susceptibility and viral fitness of patient-derived IN viruses. Maintaining patients on failing cART promotes the selection of fitter resistant strains, and thereby limits future therapy options.

SUBMITTER: Martin SA 

PROVIDER: S-EPMC8470981 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC4907232 | biostudies-literature
2023-11-30 | E-MTAB-13563 | biostudies-arrayexpress
2019-07-29 | E-MTAB-8153 | biostudies-arrayexpress
| S-EPMC4645309 | biostudies-literature
| EMPIAR-10642 | biostudies-other
| S-EPMC6070896 | biostudies-literature
| S-EPMC114002 | biostudies-literature
| S-EPMC6816933 | biostudies-literature
| S-EPMC3399858 | biostudies-literature
| S-EPMC4302432 | biostudies-literature