Tracking HIV evolution from birth to death

By Mike Nagle

- Last updated on GMT

Related tags: Aids, Evolution

A group of US researchers have tracked how HIV evolves over the
course of a person's lifetime and the findings could pave the way
for new drugs that combat the disease before it can kill.

The University of Florida team tracked four children with HIV, taking blood samples at birth, throughout life and just after they died, when they also took tissue samples. They were keen to find out how the virus mutates into a more deadly form as HIV gives way to full-blown AIDS. Previous studies have relied on cell cultures or animal experiments and this team are among the first to follow the virus in human patients. In order for the virus to infect a human cell, an 'envelope' protein on its surface, called gp120, must bind to a cell surface protein called CD4 and also the chemokine receptors CCR5 or CXCR4. Pfizer recently had Selzentry/Celsentri (maraviroc) - the world's first drug to target and block CCR5 - approved by regulators. The pharma giant decided on this target as the R5 version of HIV is predominant in early and chronic infection. The X4 virus, which uses CXCR4 to enter the cell, appears on the scene later in about half of patients with HIV-1 subtype B and is associated with onset of full blown AIDS. "The general dogma has always been that the X4 viruses are more pathogenic than the R5 viruses. And that really isn't true. People die from the R5 viruses,"​ said Maureen Goodenow, senior author of the PLoS One paper describing the study. "But certainly evolution of these X4 viruses is not a good prognostic indicator. So if we could understand the selective pressures that push viruses to develop like that, and the steps involved in the conversion of viruses, then we might be able to set up new targets for drug development."​ To do this, the scientists used a high resolution computational technique, called 'phylodynamics', to monitor mutations in gp120 and find out when and where the X4 virus first appears. Phylodynamics is the study of how pathogen genetic variation, modulated by host immunity, transmission bottlenecks, and epidemic dynamics, determines the wide variety in pathogen evolutionary development (phylogeny). In order to study it, scientists must meld together the fields of immunodynamics, epidemiology, and evolutionary biology. "We found that the late-stage viruses, the X4 viruses, were localized predominantly in the thymus [the small organ located behind the sternum that is responsible for immune T cell development],"​ Goodenow said. "It says that the thymus is the place where these viruses develop, or at least where they're localised and replicate."​ The development of X4 virus' appeared to be a sequential process of evolution directly from the R5 version. First, the early virus mutates in the V1-V2 and C2 domains of gp120. This occurs through a 'positive selection' process for the virus - meaning only the fittest viral species survive. Then, and only then, do V3 mutants emerge. It is these final stage mutations that change the co-receptor the virus uses for entry into the cell from CRC5 to CXCR4 and lead to its classification as the X4 virus. However, the researchers also found that R5 viruses remain even after the emergence of CXCR4-using strains. All of these occurred independently of any variations in the parents' medical histories. "We're starting to see what looks like a program of virus development over time. And it doesn't matter who the person is. And it doesn't matter what the time scale is,"​ explained Goodenow. "It's raising the possibility that, in fact, the evolutionary track of the virus is not totally random. There could be a real developmental program that the virus goes through." ​Although there have been recent drug advances that can prevent mother-to-child transmission of HIV, they came too late for the children in this study. They received minimal medication and all developed full-blown AIDS by their first birthdays. Therefore, the results seen are in the absence of any effects caused by antiretroviral therapy. Clearly, the next step will be to track the evolution of HIV in adults before and after treatment. Goodenow hopes their findings will ultimately pave the way for new drugs that interfere with the virus' ability to evolve in the thymus.

Related topics: Preclinical Research

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