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
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- 作者：Kristof Theys (1)
Koen Deforche (2)
Jurgen Vercauteren (1)
Pieter Libin (2)
David AMC van de Vijver (3)
Jan Albert (4)
Birgitta ?sj? (5)
Claudia Balotta (6)
Marie Bruckova (7)
Ricardo J Camacho (8) (9)
Bonaventura Clotet (10)
Suzie Coughlan (11)
Zehava Grossman (12)
Osamah Hamouda (13)
Andrzei Horban (14)
Klaus Korn (15)
Leondios G Kostrikis (16)
Claudia Kücherer (13)
Claus Nielsen (17)
Dimitrios Paraskevis (18)
Mario Poljak (19)
Elisabeth Puchhammer-Stockl (20)
Chiara Riva (6)
Lidia Ruiz (10)
Kirsi Liitsola (21)
Jean-Claude Schmit (22)
Rob Schuurman (23)
Anders S?nnerborg (24)
Danica Stanekova (25)
Maja Stanojevic (26)
Daniel Struck (22)
Kristel Van Laethem (1)
Annemarie MJ Wensing (23)
Charles AB Boucher (23) (3)
Anne-Mieke Vandamme (1) (8) - 刊名：Retrovirology
- 出版年：2012
- 出版时间：December 2012
- 年：2012
- 卷：9
- 期：1
- 全文大小：259KB
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Koen Deforche (2)
Jurgen Vercauteren (1)
Pieter Libin (2)
David AMC van de Vijver (3)
Jan Albert (4)
Birgitta ?sj? (5)
Claudia Balotta (6)
Marie Bruckova (7)
Ricardo J Camacho (8) (9)
Bonaventura Clotet (10)
Suzie Coughlan (11)
Zehava Grossman (12)
Osamah Hamouda (13)
Andrzei Horban (14)
Klaus Korn (15)
Leondios G Kostrikis (16)
Claudia Kücherer (13)
Claus Nielsen (17)
Dimitrios Paraskevis (18)
Mario Poljak (19)
Elisabeth Puchhammer-Stockl (20)
Chiara Riva (6)
Lidia Ruiz (10)
Kirsi Liitsola (21)
Jean-Claude Schmit (22)
Rob Schuurman (23)
Anders S?nnerborg (24)
Danica Stanekova (25)
Maja Stanojevic (26)
Daniel Struck (22)
Kristel Van Laethem (1)
Annemarie MJ Wensing (23)
Charles AB Boucher (23) (3)
Anne-Mieke Vandamme (1) (8)
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 Doen?as 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, kragujevac, 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 - ISSN：1742-4690
文摘
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.