Persistence of Transmitted HIV-1 Drug Resistance Mutations Associated with Fitness Costs and Viral Genetic Backgrounds

Abstract

Transmission of drug-resistant pathogens presents an almost-universal challenge for fighting infectious diseases. Transmitted drug resistance mutations (TDRM) can persist in the absence of drugs for considerable time. It is generally believed that differential TDRM-persistence is caused, at least partially, by variations in TDRM-fitness-costs. However, in vivo epidemiological evidence for the impact of fitness costs on TDRM-persistence is rare.Here, we studied the persistence of TDRM in HIV-1 using longitudinally-sampled nucleotide sequences from the Swiss-HIV-Cohort-Study (SHCS). All treatment-naïve individuals with TDRM at baseline were included. Persistence of TDRM was quantified via reversion rates (RR) determined with interval-censored survival models. Fitness costs of TDRM were estimated in the genetic background in which they occurred using a previously published and validated machine-learning algorithm (based on in vitro replicative capacities) and were included in the survival models as explanatory variables.In 857 sequential samples from 168 treatment-naïve patients, 17 TDRM were analyzed. RR varied substantially and ranged from 174.0/100-person-years;CI=[51.4, 588.8] (for 184V) to 2.7/100-person-years;[0.7, 10.9] (for 215D). RR increased significantly with fitness cost (increase by 1.6[1.3,2.0] per standard deviation of fitness costs). When subdividing fitness costs into the average fitness cost of a given mutation and the deviation from the average fitness cost of a mutation in a given genetic background, we found that both components were significantly associated with reversion-rates.Our results show that the substantial variations of TDRM persistence in the absence of drugs are associated with fitness-cost differences both among mutations and among different genetic backgrounds for the same mutation.

Deep Sequencing of HIV-1 RNA and DNA in Newly Diagnosed Patients with Baseline Drug Resistance Showed No Indications for Hidden Resistance and Is Biased by Strong Interference of Hypermutation

“…Fitness-driven selection may result in the disappearance of a resistant variant that initially caused the infection to levels below the limit of detection of population sequencing (6)(7)(8)(9)(10)(11). Because of that, the choice of a first-line treatment regimen in patients with some indications of resistance is often based on a worst-case scenario, whereby the presence of additional mutations is presumed.…”

“…Resistant viruses that initially caused the infection may be overgrown, with time and in the absence of drugs, by fitter variants that lack all or part of the resistance mutations as a result of back mutation (6)(7)(8)(9)(10)(11). The highest rates of disappearance have been recorded for the NRTI mutation M184V/I (11)(12)(13) and for the thymidine analogue-associated mutations K70R and T215Y (11).…”

“…The highest rates of disappearance have been recorded for the NRTI mutation M184V/I (11)(12)(13) and for the thymidine analogue-associated mutations K70R and T215Y (11). Back mutation may result in replacement of the resistance mutation with the original wild-type amino acid or in the introduction of an alternative amino acid.…”

HIV-1 genotypic drug resistance testing: digging deep, reaching wide?

“…In RRS, the rarely observed M184V in recently infected patients is most often transmitted from patients failing virologically, even though therapy-naïve patients seem to be the major source of new infections and therefore of TDR [56]. M184V has a high fitness cost, and thus its reversal and gradually decay in a drug-free environment prevents its onward transmission, by contrast to low fitness cost drug resistance mutations, such as M41L, T215 revertants and K103N [57 ]. This might explain why sensitive testing does not always result in higher TDR rates in chronically infected patients [58 ].…”

Epidemic Trend of HIV-1 Drug-Resistant Mutations Isolated From HIV-Infected Patients in Hebei, China from 2008 to 2013

“…However, HIV-1 evolves rapidly and ART can lead to acquired mutations that confer drug resistance. Importantly, transmission of resistant HIV-1 strains may cause severe clinical and epidemiological problems, while therapeutic failure resulting from drug resistant HIV-1 strains has become a major factor that limits successful antiviral treatments [3,4]. As such, surveillance of HIV-1 mutations that do not respond to ART may provide additional information that could guide novel drug development and treatment strategies.…”