HIV's influence on TB evolution

Tuberculosis (TB) remains a major global health problem, with 10 million cases and 2 million deaths per year according to the World Health Organization. The only available vaccine is effective in children, but its effect wanes in older children and adults.

People who are already infected with HIV are more susceptible to TB infection, and they often encounter severe complications and experience a much higher mortality rate as a result of their co-infection. The brunt of the co-epidemic of HIV and TB is especially felt in sub-Saharan Africa, a region that also struggles with high rates of poverty and inequality.

While the TB bacteria (Mycobacterium tuberculosis) has been evolving with humans for thousands of years, HIV co-infections create immunological environments within the host that this bacterium has not encountered before and could, therefore, be nudging it to evolve new characteristics.

The investigation

In one of the first studies to have investigated this possibility, Dr Anastasia Koch from UCT’s Institute of Infectious Disease and Molecular Medicine conducted an evolutionary analysis of M. tuberculosis full genome sequences from HIV uninfected and HIV co-infected individuals. She conducted her research under the supervision of Professor Robert Wilkinson from the Wellcome Centre for Infectious Disease Research in Africa and Associate Professor Darren Martin from Computational Biology, and in collaboration with colleagues from the Institute of Infectious Disease and Molecular Medicine and from the Swiss Tropical and Public Health Institute.

These M. tuberculosis strains were isolated from individuals living in Khayelitsha, a community with among the highest HIV and TB infection rates in the world.

The research team uncovered specific sites within M. tuberculosis genomes where the bacterium may have been forced to evolve in response to HIV co-infections.

Of particular significance was that when these sites were classified according to their function, an unusually large number occurred in parts of the M. tuberculosis genome that provide the genetic information for epitopes. Epitopes are the parts of M. tuberculosis proteins that are recognised by the B and T cells in the human immune system. However, in this study only epitopes that might be recognised by T cells were investigated.

“This is the first time that evolutionary models have been applied to M. tuberculosis whole genome sequence data to detect natural selection that might be influenced by HIV co-infection. An important finding of this work is that natural selection on M. tuberculosis can be detected using these methods, and that HIV may be impacting how M. tuberculosis is presently evolving,” said Koch.

The future

“The influence of HIV on M. tuberculosis epitope evolution could have implications for the design of vaccines to be administered in settings with high rates of HIV-associated TB. However, it is highly desirable that our results are validated on larger datasets in other settings to establish how generalisable our findings are,” she said.

“So it’s extremely important to stress that this requires a lot more work: firstly, to validate our findings in larger cohorts; secondly, to understand exactly how M. tuberculosis is changing during HIV co-infection; and thirdly, to understand how much of an impact this would have on immune recognition of M. tuberculosis.”

Koch hopes that the work will inform thinking around the potential for M. tuberculosis to evolve not just in response to human interventions such as the antibiotics or vaccines that have been used to control this bacterium, but also in response to the largely uncontrollable and ever-changing microbial communities that share humans as their preferred homes.

The research team’s findings appear in the advanced online edition of Molecular Biology and Evolution.