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 infectedpatient is not well understood. Major drug resistance mutations severely impair viral fitnessin 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 aftertransmission. While compensatory mutations increase fitness during treatment, theirpresence may also modulate viral fitness and virulence in absence of therapy and majorresistance mutations. We previously designed a modeling technique that quantifiesgenotypic footprints of in vivo treatment selective pressure, including both drug resistancemutations and polymorphic compensatory mutations, through the quantitative description ofa fitness landscape from virus genetic sequences. RESULTS: Genotypic correlates of viral load and CD4 cell count were evaluated in subtype Bsequences from recently diagnosed treatment-naive patients enrolled in the SPREADprogramme. The association of surveillance drug resistance mutations, reported compensatory mutations and fitness estimated from drug selective pressure fitnesslandscapes with baseline viral load and CD4 cell count was evaluated using regressiontechniques. Protease genotypic variability estimated to increase fitness during treatment wasassociated 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 highlypolymorphic positions. By contrast, treatment-related mutations in reverse transcriptasecould not explain viral load or CD4 cell count variability. CONCLUSIONS: These results suggest that polymorphic compensatory mutations in protease, reported to beselected during treatment, may improve the replicative capacity of HIV-1 even in absence ofdrug selective pressure or major resistance mutations. The presence of this polymorphicvariation may either reflect a history of drug selective pressure, i.e. transmission from atreated patient, or merely be a result of diversity in wild-type virus. Our findings suggestthat transmitted drug resistance has the potential to contribute to faster disease progressionin the newly infected host and to shape the HIV-1 epidemic at a population level