In ecology, disease tolerance is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen weight. found that homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference buy 480449-71-6 in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is usually a feature of contamination 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 recognized, but no tolerance genes are known. Using statistical techniques originating from herb ecology, we analyzed data from an HIV cohort to buy 480449-71-6 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 contamination. We also observed that individuals Rabbit Polyclonal to SCNN1D 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 infections. Introduction In response to pressure by pathogens, host populations can evolve in two ways: They can develop either resistance or tolerance to the disease [1]C[8]. Resistance mechanisms reduce the pathogen burden. Tolerance mechanisms, in contrast, reduce the damage that accompanies contamination without affecting the pathogen directly. One of the best examples for tolerance are sooty mangabeys infected with Simian Immunodeficiency Computer virus (SIV), whichdespite harboring high computer virus loadsdo not develop disease [9]. Whether hosts evolve resistance or tolerance affects the evolutionary trajectory of host-pathogen systems [2],[3],[10]C[12]. The development of resistance genes in the host provokes counteradaptations of the pathogen that overcome host resistance, resulting in an endless arms race. In contrast, tolerance genes benefit both the host and the pathogen and are therefore predicted to fix. It is progressively acknowledged that disentangling resistance and tolerance not only advances our understanding of the coevolution between hosts and pathogens but also is relevant clinically [13]. Like resistance factors, mechanisms of tolerance, once recognized, can be exploited for therapy. In contrast to resistance-based therapy, tolerance-based treatment does not aim at reducing the pathogen weight but rather at ensuring the well-being of the host. For that reason, tolerance-based therapy is also hypothesized to be evolution-proofthat is usually, not to select for drug-resistant pathogens [4],[5],[14]. It has been argued, however, that this pathogen populace might evolve higher virulence in response to tolerance-based treatment [3],[15],[16]. Although numerous review papers have been written around the potential benefits of tolerance research [1]C[8], the formal framework for disentangling tolerance and resistance has not been applied to many animal disease systems. There is a paradigmatic study on mouse malaria [17] and a few on insects [18]C[20]. But a quantitative tolerance analysis has, to our knowledge, not yet been conducted for any clinically relevant human disease. In this study, we apply such an analysis to HIV contamination in humans. Formally, tolerance can be quantified as the switch in disease progression across different levels of pathogen burden (observe Physique 1A) [2],[4]. In the context of HIV, excellent steps of disease progression and pathogen burden are available (observe Figures 1B and ?and2A).2A). A few weeks after infection, HIV attains a level in the plasma of infected individuals that is usually approximately stable over several buy 480449-71-6 years. This level, called the set-point viral weight, is very well suited as a proxy for the parasite burden necessary for a formal tolerance analysis. Physique 1 Quantifying tolerance and resistance. Figure 2 Relationship between CD4+ T-cell decline and set-point viral weight in our study population. The.