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

Kristof Theys*, Koen Deforche, Jurgen Vercauteren, Pieter Libin, David A.M.C. van de Vijver, Jan Albert, Birgitta Åsjö, Claudia Balotta, Marie Bruckova, Ricardo J. Camacho, Bonaventura Clotet, Suzie Coughlan, Zehava Grossman, Osamah Hamouda, Andrzei Horban, Klaus Korn, Leontios G. Kostrikis, Claudia Kücherer, Claus Nielsen, Dimitrios ParaskevisMario Poljak, Elisabeth Puchhammer-Stockl, Chiara Riva, Lidia Ruiz, Kirsi Liitsola, Jean Claude Schmit, Rob Schuurman, Anders Sönnerborg, Danica Stanekova, Maja Stanojevic, Daniel Struck, Kristel Van Laethem, Annemarie M.J. Wensing, Charles A.B. Boucher, Anne Mieke Vandamme, E. Puchhammer-Stockl, M. Sarcletti, B. Schmied, M. Geit, G. Balluch, J. Vercauteren, I. Derdelinckx, A. Sasse, M. Bogaert, H. Ceunen, A. De Roo, S. De Wit, K. Deforche, F. Echahidi, on behalf of the SPREAD-programme

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    23 Citations (Scopus)


    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.Conclusions: These results suggest that polymorphic compensatory mutations in protease, reported to be selected during treatment, may improve the replicative capacity of HIV-1 even in absence of drug selective pressure or major resistance mutations. The presence of this polymorphic variation may either reflect a history of drug selective pressure, i.e. transmission from a treated patient, or merely be a result of diversity in wild-type virus. Our findings suggest that transmitted drug resistance has the potential to contribute to faster disease progression in the newly infected host and to shape the HIV-1 epidemic at a population level.

    Original languageEnglish
    Article number81
    Publication statusPublished - 3 Oct 2012


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