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

Supang A Martin,Patricia A Cane,Jean L Mbisa,Deenan Pillay

doi:10.3390/pathogens10091070

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.

Highlights

Since the introduction of combination antiretroviral therapy against HIV-1 in the late 1990s, the number of overall new HIV infections and AIDS-related deaths has decreased [1]
Little is known about the full effects and coevolution of drug resistance in the full-length HIV-1 pol gene, the target of the four main classes of ARVs used in combination antiretroviral therapy (cART): protease inhibitor (PI), nucleos(t)ide reverse transcriptase inhibitor (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and Integrase strand transfer inhibitors (InSTIs)
We investigate the effect on InSTI susceptibility and viral fitness of patient-derived IN only or in combination with coevolved PR and RT, using a single-replication-cycle drug susceptibility assay

Summary

Introduction

Since the introduction of combination antiretroviral therapy (cART) against HIV-1 in the late 1990s, the number of overall new HIV infections and AIDS-related deaths has decreased [1]. Not much is known about the effects of different combinations of PI, RTI and InSTI resistance mutations on overall drug susceptibility and viral fitness. These data may be important in informing how best to use drugs targeting all three genes in clinical practice. We use a full-length pol single-genome sequencing assay to investigate the development, evolution and linkage of PI, RTI and InSTI resistance mutations in a patient undergoing InSTI-containing therapy. We investigate the effect on InSTI susceptibility and viral fitness of patient-derived IN only or in combination with coevolved PR and RT, using a single-replication-cycle drug susceptibility assay

Methods

Results

Conclusion