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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 Theys1*, Koen Deforche2, Jurgen Vercauteren1, Pieter Libin2, David AMC van de Vijver3, Jan Albert4, Birgitta Åsjö5, Claudia Balotta6, Marie Bruckova7, Ricardo J Camacho89, Bonaventura Clotet10, Suzie Coughlan11, Zehava Grossman12, Osamah Hamouda13, Andrzei Horban14, Klaus Korn15, Leondios G Kostrikis16, Claudia Kücherer13, Claus Nielsen17, Dimitrios Paraskevis18, Mario Poljak19, Elisabeth Puchhammer-Stockl20, Chiara Riva6, Lidia Ruiz10, Kirsi Liitsola21, Jean-Claude Schmit22, Rob Schuurman23, Anders Sönnerborg24, Danica Stanekova25, Maja Stanojevic26, Daniel Struck22, Kristel Van Laethem1, Annemarie MJ Wensing23, Charles AB Boucher233, Anne-Mieke Vandamme18 and on behalf of the SPREAD-programme

Author Affiliations

1 Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

2 MyBioData, Rotselaar, Belgium

3 Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands

4 Clinical Microbiology, Karolinska University Hospital and Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden

5 Section for Microbiology and Immunology, Gade institute, University of Bergen, Bergen, Norway

6 University of Milan, Milan, Italy

7 National Institute of Public Health, Prague, Czech Republic

8 Centro de Malária e outras Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal

9 Centro Hospitalar de Lisboa Ocidental, Lisbon, Portugal

10 irsiCaixa AIDS Research Institute & Lluita contra la SIDA Foundation, Hospital Universitari “Germans Trias i Pujol”, Badalona, Spain

11 University College Dublin, Dublin, Ireland

12 Sheba Medical Center, Tel-Hashomer, and School of Public Health, Tel-Aviv University, Tel-Aviv, Israel

13 Robert-Koch Institute, Berlin, Germany

14 Warsaw Medical University and Hospital for Infectious Diseases, Warsaw, Poland

15 Institut für Klinische und Molekulare Virologie, University of Erlangen, Erlangen, Germany

16 University of Cyprus, Nicosia, Cyprus

17 Statens Serum Institute, Copenhagen, Denmark

18 National Retrovirus Reference Center, Department of Hygiene Epidemiology of Medical Statistics, University of Athens, Medical School, Athens, Greece

19 University of Ljubljana, Ljubljana, Slovenia

20 Medical University of Vienna, Vienna, Austria

21 National Institute of Health and Welfare, Helsinki, Finland

22 Centre Hospitalier de Luxembourg and Centre de Recherche Public de la Santé, Luxembourg, Luxembourg

23 Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, the Netherland

24 Divisions of Infectious Diseases and Clinical Virology, Karolinska Institutet, Stockholm, Sweden

25 Slovak Medical University, Bratislava, Slovak Republic

26 School of Medicine, University of Belgrade, Belgrade, Serbia

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Retrovirology 2012, 9:81  doi:10.1186/1742-4690-9-81

Published: 3 October 2012



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.


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.


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.