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 acrossHLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-Bhomozygotes 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.
Author Summary
When confronted with pathogens, hosts can either evolve to fight them or learn to live with them. The first of these two strategies is called “resistance” and the second “tolerance”. In the context of HIV, many genes conferring resistance have been identified, but no tolerance genes are known. Using statistical techniques originating from plant ecology, we analyzed data from an HIV cohort to look for differences in tolerance between HIV-infected individuals and tested whether they go hand in hand with genetic differences. We found that younger people are more tolerant to HIV infection. We also observed that individuals who carry two different alleles of HLA-B, an important immunity gene, are more tolerant. These findings add to our understanding of how hosts tolerate infections and could open new avenues for treating
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