Disentangling human tolerance and resistance against HIV

PLoS Biol. 2014 Sep 16;12(9):e1001951. doi: 10.1371/journal.pbio.1001951. eCollection 2014 Sep.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age Factors
  • Alleles
  • CD4 Lymphocyte Count
  • Cohort Studies
  • Disease Progression
  • Female
  • Gene Frequency
  • Genome, Human
  • HIV Infections / genetics
  • HIV Infections / immunology*
  • HIV Infections / pathology
  • HIV Infections / virology
  • HIV-1 / immunology*
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology*
  • Heterozygote
  • Homozygote
  • Host-Pathogen Interactions
  • Humans
  • Immune Tolerance / genetics*
  • Immunity, Innate / genetics*
  • Male
  • Middle Aged
  • Polymorphism, Genetic*
  • Receptors, CCR5 / genetics
  • Receptors, CCR5 / immunology
  • Sex Factors
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • T-Lymphocytes / virology
  • Viral Load

Substances

  • CCR5 protein, human
  • HLA-B Antigens
  • Receptors, CCR5

Grants and funding

RRR acknowledges the financial support of the Swiss National Science Foundation (grant number: 315230-130855). This study has been performed within the framework of the Swiss HIV Cohort Study, supported by the Swiss National Science Foundation (grant number 33CS30_148522), and was further supported by SHCS project 697 and the SHCS research foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.