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.

Originele taal-2English
Aantal pagina's13
StatusPublished - 3 okt 2012

Bibliografische nota

Funding Information:
We wish to thank Robert Shafer and Soo-Yon Rhee that maintain the Stanford HIV-1 Drug Resistance Database and Ana Carolina Marques Palma for carefully reading the manuscript. Researchers and clinicians that made data available for the study within the SPREAD Programme. Austria: E. Puchhammer-Stockl (national coordinator), M. Sarcletti, B. Schmied, M. Geit, and G. Balluch. Belgium: A.-M. Vandamme (national coordinator), J. Vercauteren, I. Derdelinckx, A. Sasse, M. Bogaert, H. Ceunen, A. De Roo, S. De Wit, K. Deforche, F. Echahidi, K. Fransen, J.-C. Goffard, P. Goubau, E. Goudeseune, J.-C. Yombi, P. Lacor, C. Liesnard, M. Moutschen, D. Pierard, R. Rens, Y. Schrooten, D. Vaira, A. Van den Heuvel, B. Van Der Gucht, M. Van Ranst, E. Van Wijngaerden, B. Vandercam, M. Vekemans, C. Verhofstede, N. Clumeck, and K. Van Laethem. Cyprus: L. Kostrikis (national coordinator), I. Demetriades, I. Kousiappa, V. Demetriou, and J. Hezka. Czech Republic: Marek Linka (national coordinator), M. Bruckova and L. Machala. Denmark: C. Nielsen (national coordinator), L. B. Jrgensen, J. Gerstoft, L. Mathiesen, C. Pedersen, H. Nielsen, A. Laursen, and B. Kvinesdal. Finland: K. Liitsola (national coordinator), M. Ristola, J. Suni, and J. Sutinen. Germany: K.Korn (national coordinator), C. Kücherer, T. Berg, P. Braun, G. Poggensee, M. Daümer, J. Eberle, O. Hamouda, H. Heiken, R. Kaiser, H. Knechten, H. Müller, S. Neifer, B. Schmidt, H. Walter, B. Gunsenheimer-Bartmeyer, and T. Harrer. Greece: A. Hatzakis (national coordinator), D. Paraskevis, E. Magiorkinis, E. Hatzitheodorou, C. Issaris, C. Haida, A. Zavitsanou, G. Magiorkinis, M. Lazanas, M. Chini, N. Magafas, N. Tsogas, V. Paparizos, S. Kourkounti, A. Antoniadou, A. Papadopoulos, P. Panagopoulos, G. Poulakou, V. Sakka, G. Chryssos, S. Drimis, P. Gargalianos, M. Lelekis, G. Xilomenos, M. Psichogiou, G. L. Daikos, G. Panos, G. Haratsis, T. Kordossis, A. Kontos, G. Koratzanis, M. Theodoridou, G. Mostrou, and V. Spoulou. Ireland: W. Hall (national coordinator), C. De Gascun, C. Byrne, M. Duffy, C. Bergin, D. Reidy, G. Farrell, J. Lambert, E. O’Connor, A. Rochford, J. Low, P. Coakely, and S. Coughlan. Israel: Z. Grossman (national coordinator), I. Levi, and D. Chemtob. Italy: C. Balotta (national coordinator), C. Riva, C. Mussini, I. Caramma, A. Capetti, M. C. Colombo, C. Rossi, F. Prati, F. Tramuto, F. Vitale, M. Ciccozzi, G. Angarano, and G. Rezza. Luxembourg: J. C. Schmit (national coordinator), D. Struck, R. Hemmer, V. Arendt, T. Staub, F. Schneider, and F. Roman. The Netherlands: A. M. J. Wensing (national coordinator), C. A. B. Boucher (national coordinator), D. A. M. C. van de Vijver, P. H. M. van Bentum, K. Brinkman, E. L. op de Coul, M. E. van der Ende, I. M. Hoepelman, M. van Kasteren, J. Juttmann, M. Kuipers, N. Langebeek, C. Richter, R. M. W. J. Santegoets, L. Schrijnders-Gudde, R. Schuurman, and B. J.M. van de Ven. Norway: B. Åsjö (national coordinator), V. Ormaasen, and P. Aavitsland. Poland: A. Horban (national coordinator), J. J. Stanczak, G. P. Stanczak, E. Firlag-Burkacka, A. Wiercinska-Drapalo, E. Jablonowska, E. Malolepsza, M. Leszczyszyn-Pynka, and W. Szata. Portugal: R. Camacho (national coordinator), C. Palma, F. Borges, T. Paixão, V. Duque, and F. Araújo on behalf of the Portuguese SPREAD Network. Republic of Serbia: M. Stanojevic (national coordinator), Dj. Jevtovic, and D. Salemovic. Slovakia: D. Stanekova (national coordinator), M. Habekova, M. Mokras, and P. Truska. Slovenia: M. Poljak (national coordinator), D. Babic, J. Tomazic, L. Vidmar, and P. Karner. Spain: B. Clotet (national coordinator), C. Gutiérrez, C. de Mendoza, I. Erkicia, P. Domingo, X. Camino, M. J. Galindo, J. L. Blanco, M. Leal, A. Masabeu, A. Guelar, J. M. Llibre, N. Margall, J. A. Iribarren, S. Gutierrez, J. F. Baldoví, J. D. Pedreira, J. M. Gatell, S. Moreno, C. de Mendoza, V. Soriano, and L. Ruiz on behalf of the Maraton TV Study Group. Sweden: J. Albert (national coordinator), A. Blaxhult, A. Heidarian, A. Karlsson, K. Aperia-Peipke, I.-M. Bergbrant, M. Gisslén, B. Svennerholm, P. Björkman, G. Bratt, M. Carlsson, H. Ekvall, M. Ericsson, M. Höfer, B. Johansson, A. Sonnerbörg, N. Kuylenstierna, B. Ljungberg, S. Mäkitalo, A. Strand, and S. Öberg. Kristof Theys was funded by a PhD grant of the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT) and received funding from Research Fund (PDM) of the KU Leuven and from the Research Foundation - Flanders (FWO). This work was supported in part by the Virolab project (EU IST STREP Project 027446), European Community’s Seventh Framework Programme (FP7/2007-2013) under the project “Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN)” - grant agreement nr 223131, EURESIST 6FP (IST-2004-027173), by the AIDS Reference Laboratory of Leuven that receives support from the Belgian Ministry of Social Affairs through a fund within the Health Insurance System, European Commission (grant QLK2CT200101344, fifth framework; grant LSHPCT2006518211, sixth framework); Belgian AIDS Reference Laboratory Fund, the Research Foundation - Flanders (FWO) - Flanders (grants G.0611.09 and K8.012.12N); the Interuniversity Attraction Poles Programme, Belgian State, Belgian Science Policy (IAP-VI P6/41); Cyprus Research Promotion Foundation (grant Health/0104/22); Danish AIDS Foundation; Ministry of Health (Germany; grant 150268618); Ministry of Education and Research (Germany; grant 01KI501); Fifth National Program on HIV/AIDS, Instituto Superiore di Sanita (Italy; grants N 40F.56 and 20D.1.6); Fondation Recherche sur le SiDA; Ministry of Health (Luxembourg); Swedish Research Council; Maraton TV3 Fundation (Spain; grant 021730); Ministry of Education and Science, Serbia, grant No 175024.


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