title: Disentangling human tolerance and resistance against HIV.
abstract: In ecology, "disease tolerance" is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis.
authors.affiliation: Institute of Integrative Biology, ETH Zurich, Zurich, Switzerland.
authors.forename: Roland R
authors.initials: RR
authors.lastname: Regoes
authors.affiliation: Global Health Institute, EPF Lausanne, Lausanne, Switzerland; Institute of Microbiology, University of Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: McLaren
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, University of Basel, Basel, Switzerland.
authors.forename: Manuel
authors.initials: M
authors.lastname: Battegay
authors.affiliation: Division of Infectious Diseases, Regional Hospital Lugano, Lugano, Switzerland.
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Geneva University Hospital, HIV Unit, Department of Internal Medicine, Geneva, Switzerland.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Calmy
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.affiliation: Division of Infectious Diseases and Hospital Epidemiology, Cantonal Hospital St.Gallen, St.Gallen, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: University Clinic of Infectious Diseases, University Hospital Bern and University of Bern, Bern, Switzerland.
authors.forename: Andri
authors.initials: A
authors.lastname: Rauch
authors.affiliation: Institute of Microbiology, University of Lausanne, Lausanne, Switzerland.
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.affiliation: Global Health Institute, EPF Lausanne, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Jacques
authors.initials: J
authors.lastname: Fellay
mesh_terms: D000328:Adult; D000367:Age Factors; D000483:Alleles; D018791:CD4 Lymphocyte Count; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D015894:Genome, Human; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D006579:Heterozygote; D006720:Homozygote; D054884:Host-Pathogen Interactions; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics*; D007113:Immunity, Innate / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics / Q000276:immunology; D012737:Sex Factors; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology; D019562:Viral Load
chemical_list: C584933:CCR5 protein, human; D015235:HLA-B Antigens; D019713:Receptors, CCR5