The researchers say that their findings may pave the way for new therapeutic agents that target the virus earlier in the disease process, before it takes a lethal turn.
'We were very interested in understanding how the virus mutates from the beginning of the infection until the end,' said Marco Salemi, an assistant professor of pathology, immunology and laboratory medicine in the UF College of Medicine and lead author on the study, which appeared in an online issue of the journal PLoS ONE in September.
'Previously, the only thing known was that somehow the HIV population mutates. And as soon as that happens, patients start developing AIDS. But no one knew how and where the population evolved over time,' he added.
The researchers tracked four children born with HIV. They studied their blood samples taken at birth, throughout life and just after death, when tissues samples were also taken. The mutations in a protein that enables HIV to attach to human cells were monitored by using a high-resolution computational technique.
Thereafter, the researchers categorised the virus into two groups, namely, R5 and X4. While the population of R5 virus is usually present in high numbers during the early stages of infection, the population of X4 enters the scene just before HIV gives way to full-blown AIDS. With a view to finding out when and where the telltale X4 population first appeared, the researchers tracked the viruses in each patient.
'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 paper and the Stephany W. Holloway university chair for AIDS research in the UF College of Medicine. '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,' the researcher added.
The researchers say that the study has revealed new information about the evolution of HIV, and shown that most viral changes take place in the thymus, a small organ located behind the breastbone that is responsible for immune cell development. 'We found that the late-stage viruses, the X4 viruses, were localized predominantly in the thymus. It says that the thymus is the place where these viruses develop, or at least where they're localized and replicate,' Goodenow said.
The researchers also found that HIV followed a similar path in each child, regardless of variations in the patients' medical histories. 'We are 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. 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,' Goodenow said.
Recent advances in prenatal drug therapies have substantially decreased the rates of mother-to-child transmission. However, when the study was begun eight years ago, the child subjects had received minimal medication and all developed full-blown AIDS by their first birthdays. 'Their whole virus infection was what we call the natural history. This tells you what happens in the absence of combination antiretroviral therapy,' Goodenow said.
The researchers will now track the evolution of HIV in adults before and after treatment. They hope their findings will pave the way for new drugs that interfere with the virus' ability to evolve in the thymus. 'This is an excellent study that reveals fine-scale patterns in the evolution and adaptation of HIV during infection. For the first time, it shows how the movement of immune cells with the body is linked to the evolutionary behaviour of the virus, which in turn determines the clinical outcome of infection,' said Oliver Pybus, a research fellow in the department of zoology at Oxford University.