Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naive HIV-1 infected patients

Abstract

Background:The effect of drug resistance transmission on disease progression in the newly infected patient is not well understood. Major drug resistance mutations severely impair viral fitness in a drug free environment, and therefore are expected to revert quickly. Compensatory mutations, often already polymorphic in wild-type viruses, do not tend to revert after transmission. While compensatory mutations increase fitness during treatment, their presence may also modulate viral fitness and virulence in absence of therapy and major resistance mutations. We previously designed a modeling technique that quantifies genotypic footprints of in vivo treatment selective pressure, including both drug resistance mutations and polymorphic compensatory mutations, through the quantitative description of a fitness landscape from virus genetic sequences.Results: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype B sequences from recently diagnosed treatment-naive patients enrolled in the SPREAD programme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitness landscapes with baseline viral load and CD4 cell count was evaluated using regression techniques. Protease genotypic variability estimated to increase fitness during treatment was associated with higher viral load and lower CD4 cell counts also in treatment-naive patients, which could primarily be attributed to well-known compensatory mutations at highly polymorphic positions. By contrast, treatment-related mutations in reverse transcriptase could not explain viral load or CD4 cell count variability.

Commentary on the role of treatment-related HIV compensatory mutations on increasing virulence: new discoveries twenty years since the clinical testing of protease inhibitors to block HIV-1 replication

“…I have spent the last 15 years of my research career providing evidence to support this virulence hypothesis [12,13] so the excellent article by Theys et al . [8] serves my ego well.…”

“…In the study by Theys et al . [8], lower fitness scores derived from primary drug-resistance mutations did not correlate with higher CD4 cell counts or lower viral loads in treatment-naïve patients. The fitness cost of deleterious, escape mutations within a virus appears highly dependent on the time of selection pressure, relative appearance of the escape, and the rate of subsequent diversifying evolution that can lead to compensatory mutations.…”

“…Likewise, reversion of the primary drug-resistance mutations in a background with compensatory mutations may result in HIV-1 that is actually more fit than the majority of wild-type virus: the central thesis of Theys et al . [8] If this fitness is related to virulence, infection with HIV-1 harboring PI-associated compensatory mutations may actually lead to faster disease progression as described (Figure 2) [8]. The disconcerting aspect of this hypothesis is the probable maintenance of this virulent HIV-1 throughout disease whereas deleterious mutations in a defective HIV are more likely to revert after transmission.…”

“…[8] may have provided the first in vivo evidence that some HIV-1 mutants selected under drug pressure may actually be of higher replicative fitness, which in turn could lead to higher viral loads and lower CD4 cell counts. Furthermore, it is naturally assumed that all evolutionary pathways leading to drug resistance come with a fitness cost, but this is not the case.…”

“…The effects of these secondary PI mutations has been a subject of debate for years but a recent paper by Theys et al . in Retrovirology [8] sheds new light on how these polymorphisms may impact disease progression in newly infected patients.…”