Sunday, December 14, 2014

HIV becoming less virulent

I read the article that Emi sent along about decreasing HIV virulence. In HIV infections the HIV virus faces a tradeoff between high virulence (increasing the likelihood of transmission), and reduced lifespan of the host (decreasing the likelihood of transmission). This study looked at the HLA molecules in Botswana and South African populations and used models to assess ART’s ability to accelerate the effects of HLA-mediated viral adaptation.

HLA genes are an important factor in immune control of HIV-1 infection, as they direct cytotoxic T lymphocytes against virus-infected cells. HIV can only evade this immune response by selecting for mutants that reduce the viral replicative capacity.  The authors also hypothesized that increasing the use of ART would likely remove viruses with the highest replicative capacity from the population, and also lead to a decrease in virulence overtime.

The study examined two populations of ART-naive antenatal mothers in Botswana and another in South Africa. They tested the adaptation of all HIV sequences in the populations against each individuals HLA molecules. To assess whether the frequency of cytotoxic T lymphocyte mutants would increase over a decade, the researchers looked at a second cohort enrolled ten years later at the same site in South Africa.  The authors also created a mathematical model to assess the effects of ART.

This study suggests that even within a decade, the population-wide effects of HIV evolution are evident. The findings show that there is a lack of HLA-B*57 associated protective effect in the Botswana population. This suggests that HLA B and HLA-B*57 are important drivers in the HIV selection, with predictable losses in immune protection. Consistent with the author’s hypothesis, they found a lower viral replicative capacity in the Botswana population compared to the South African population. Although there was an increase in the number of HLA-B*57 mutants in the Botswana subset for which viral replicative capacity measurements were taken, the number of these mutants did not correlate significantly with the viral replicative capacity, which suggests that additional factors are in play.

The authors believe that one factor is the increased diversity of HLA-associated mutations in the Botswana population compared to the South African population.
Another factor to consider is the effect of ART. The study hypothesizes that giving ART to people with low CD4 counts tends to accelerate the evolution of variants with lower viral replicative capacity. The authors’ model suggests increased use of ART also aids in lowering the virulence of HIV. 

The study’s findings have important implications and extrapolated to an individual level, it may mean that more people’s immune system will be able to control disease for longer. If scientists can understand what is required to control the virus, it may help with development of better antivirals or a vaccine. In the very long run, this could help us eradicate the infection.

Remaining questions include what made the North American population that demonstrated a contrary finding to this study different from the Botswana and South African populations these researchers studied? Are these two populations in Botswana and South Africa representative of what is happening worldwide? The authors state, “epidemics in new hosts diminish in virulence over time?” Is this true for other epidemics?  

Thanks to Emi for passing this article on and for an interesting read!

By Olivia

Payne, Rebecca et al. “Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence.” PNAS Early Ed., received for review July 15, 2014, approved Oct. 31, 2014.    

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