title: 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.
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 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium. kristof.theys@uzleuven.be
authors.forename: Kristof
authors.initials: K
authors.lastname: Theys
authors.forename: Koen
authors.initials: K
authors.lastname: Deforche
authors.forename: Jurgen
authors.initials: J
authors.lastname: Vercauteren
authors.forename: Pieter
authors.initials: P
authors.lastname: Libin
authors.forename: David Amc
authors.initials: DA
authors.lastname: van de Vijver
authors.forename: Jan
authors.initials: J
authors.lastname: Albert
authors.forename: Birgitta
authors.initials: B
authors.lastname: Asjö
authors.forename: Claudia
authors.initials: C
authors.lastname: Balotta
authors.forename: Marie
authors.initials: M
authors.lastname: Bruckova
authors.forename: Ricardo J
authors.initials: RJ
authors.lastname: Camacho
authors.forename: Bonaventura
authors.initials: B
authors.lastname: Clotet
authors.forename: Suzie
authors.initials: S
authors.lastname: Coughlan
authors.forename: Zehava
authors.initials: Z
authors.lastname: Grossman
authors.forename: Osamah
authors.initials: O
authors.lastname: Hamouda
authors.forename: Andrzei
authors.initials: A
authors.lastname: Horban
authors.forename: Klaus
authors.initials: K
authors.lastname: Korn
authors.forename: Leondios G
authors.initials: LG
authors.lastname: Kostrikis
authors.forename: Claudia
authors.initials: C
authors.lastname: Kücherer
authors.forename: Claus
authors.initials: C
authors.lastname: Nielsen
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Paraskevis
authors.forename: Mario
authors.initials: M
authors.lastname: Poljak
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Puchhammer-Stockl
authors.forename: Chiara
authors.initials: C
authors.lastname: Riva
authors.forename: Lidia
authors.initials: L
authors.lastname: Ruiz
authors.forename: Kirsi
authors.initials: K
authors.lastname: Liitsola
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Schmit
authors.forename: Rob
authors.initials: R
authors.lastname: Schuurman
authors.forename: Anders
authors.initials: A
authors.lastname: Sönnerborg
authors.forename: Danica
authors.initials: D
authors.lastname: Stanekova
authors.forename: Maja
authors.initials: M
authors.lastname: Stanojevic
authors.forename: Daniel
authors.initials: D
authors.lastname: Struck
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.forename: Annemarie Mj
authors.initials: AM
authors.lastname: Wensing
authors.forename: Charles Ab
authors.initials: CA
authors.lastname: Boucher
authors.forename: Anne-Mieke
authors.initials: AM
authors.lastname: Vandamme
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008297:Male; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011446:Prospective Studies; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D014764:Viral Proteins; D010447:Peptide Hydrolases