By: Zuri Sullivan
Humans are extremely diverse. We have different skin colors, different hair colors, different personalities, different body types…in almost every characteristic, no two people are exactly the same. One of the ways in which we are most diverse, and one of the most important ways that we are diverse, is our HLA type, which stands for human leukocyte antigen. The HLA locus is actually the most polymorphic, or variable, set of genes in the human genome. Currently, the number of alleles, or types, of the two HLA classes is 9,232 for HLA class I, and 3,010 for HLA class II. Compare that to the number of skin, hair, or eye colors that exist in our species, and you can appreciate how diverse our HLA type is. From an evolutionary standpoint, this high level of diversity in our HLA alleles is crucial for the survival of our species, as HLA alleles can affect what kinds of infections or autoimmune disease we’re susceptible to. Thus, by selecting for a high level of diversity at the HLA locus, evolution has safeguarded our species against being wiped out by any one pathogen, because we each have a differential susceptibility to different pathogens.
One such pathogen is the human immunodeficiency virus (HIV), which is the leading cause of death from an infectious agent worldwide. And indeed, there are certain HLA alleles that confer protection against HIV. In particular, two alleles, HLA-B57 and HLA-B58, are strongly associated with HIV elite control, the phenomenon by which some individuals get infected with the virus but never progress to AIDS, even in the absence of anti-HIV drugs. The presence of these protective alleles really illustrates the evolutionary utility of HLA diversity—in the absence of modern medicine, these people would likely be the only ones to survive HIV infection.
Evolution is a two way street, however, and just as viruses exert evolutionary pressure on our immune system, our immune system exerts evolutionary pressure on viruses, including HIV. That’s the subject of a paper recently published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS), in which researchers from Oxford University showed that in areas with an extremely high burden of HIV, protective HLA alleles may be driving the virus to become less virulent.
What would be the advantage to the virus of becoming less virulent? In the case of viruses that kill their hosts quickly, such as Ebola, being less virulent would likely help the virus to spread. In order to infect other individuals, viruses need their host to be alive, and ideally walking around and contacting other individuals that can get infected. If a virus causes debilitating disease soon after infection, its host is less able to spread the infection to other individuals. So extremely virulent viruses, like Ebola, are actually bad for us (the host) and bad for the virus. This is why some of the most successful viruses, like rhinovirus (the cause of the common host) and influenza virus (the cause of the flu) don’t make most people extremely sick, and have managed to stick around in the population for centuries.
Another reason why a virus would become less virulent is that virulence could be a trade off for another advantage. Often when pathogens acquire mutations that allow them to resist certain evolutionary pressures, such as antibiotics or the immune system, these mutations have a fitness cost to the pathogen. But, the relative benefit of evading the immune system or antibiotics outweighs the cost of a moderate decrease in fitness. This is the hypothesis raised by Payne, et al in their PNAS paper.
They compared Botswana and South Africa, two countries with an extremely high burden of HIV, but an overall higher seroprevalence (infections per capita) in Botswana. First, they found that HIV-infected people had relatively lower viral loads than those in South Africa, suggesting that circulating viruses in Botwswana may have overall lower replicating capacity than viruses in South Africa. When they directly tested the replicative capacity of viruses isolated from 64 infected individuals in Botswana and 16 in South Africa, they confirmed that viruses from the cohort of Botswanans had lower replicative capacity. To look at whether protective HLA alleles may be playing a role in this differential viral replicative capacity, they next looked at viral mutations known to confer resistance to HLA-B57 and HLA-B58. Their results seemed consistent with their hypothesis—viruses from the Botswana cohort had a greater proportion of resistance mutations to HLA-B57 and 58 than those from the South Africa cohort. Finally, they compared a South African cohort from the early 2000s to one from 2012-13, and found that the frequency of mutations that allow HIV to escape protective HLA alleles had increased during this period, further supporting the idea that the virus is evolving resistance to these protective alleles over time.
One caveat to the findings in this study is that they were unable to find a correlation between viral replicative capacity and HLA-driven mutations. This suggests that this evolutionary relationship is more complex than was captured by their experiments, and that other factors, such as HLA diversity and antiretroviral therapy coverage, are likely important. However, other studies in South Africa have found viral replicative capacity to be correlated with the accumulation of HLA-driven mutations, supporting the overall idea that the mutations to evade the immune system come at a cost to viral fitness.
These results echo a longstanding phenomenon in the study of HIV and its close relative, siminan immunodeficiency virus (SIV), which infects non-human primates. While HIV infection in humans results in mortality rate close to 100% when untreated, many primate species, such as the African green monkey, can be infected with SIV without any apparent effect on their health. This points to the importance of host-pathogen co-evolution in disease susceptibility. HIV has infected the human population for less than a century, while SIV has been around for tens of millennia. Over that amount of time, both virus and host have evolved to resist each other without overtly killing each other. While it’s unlikely that we will see any HIV-driven evolutionary pressure on our on biology in our lifetime, it is clear our biology has placed significant pressure on the virus in its short history.