Title: Treatment-associated polymorphisms in protease are significantly associated with higher viral load and lower CD4 count in newly diagnosed drug-naïve HIV-1 infected patients
Authors: Theys, Kristof ×
Deforche, Koen
Vercauteren, Jurgen
Libin, Pieter
van de Vijver, D.
Alber, J.
Asjo, B.
Balotta, C.
Bruckova, M.
Camacho, Ricardo J.
Clotet, B.
Coughlan, S.
Grossman, Z.
Hamouda, O.
Horban, A.
Korn, K.
Kostrikis, L.G.
Kücherer, C.
Nielsen, C.
Paraskevis, Dimitrios
Poljak, M.
Puchhammer-Stockl, R.
Riva, C.
Ruiz, L.
Liitsola, L.
Schmit, J.C.
Schuurman, R.
Sönnerborg, A.
Stanekova, D.
Stanejovic, M.
Struck, D.
Van Laethem, Kristel
Wensing, AMJ
Boucher, CAB
Vandamme, Anne-Mieke #
Contributors: Van Wijngaerden, Eric
Issue Date: Oct-2012
Publisher: BioMed Central
Series Title: Retrovirology vol:9 pages:81
Article number: 81
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 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.
ISSN: 1742-4690
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Clinical Infectious and Inflammatory Disorders
Department of Microbiology & Immunology - miscellaneous
Laboratory of Clinical and Epidemiological Virology (Rega Institute)
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
2012149.pdf Published 260KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science