Science Spin January 2007

UCD virus hunter travels the world seeking answers

By Claire O Connell

There's more to Professor William Hall, UCD's Head of Medical Microbiology, than meets the eye. Sitting in his newly built Centre for Research in Infectious Diseases, Prof Hall is smartly dressed and research papers are laid out across his desk. But a quick scan of his office hints at a more adventurous, Indiana-Jones-like side to his scientific career: tribal artifacts and images reflect his global hunt for viruses among some of the world's most remote populations.

Prof Hall, a native of Co Down, was the first person to identify Human T-lymphotrophic virus type II (HTLV-II) in a human population. Since then he has tracked subtypes of the retrovirus in regions as far apart as the Amazon and Outer Mongolia. He has also used his knowledge of HTLV infection to develop a transgenic model for leukaemia.

It all started when he was in Cornell in the early 1990s, looking at HIV-infection rates in intravenous drug users in New York City. A significant proportion of the drug users appeared to be carrying another, unidentified virus and many researchers assumed it was HTLV-I.

"I developed a method to isolate the other virus," explained Prof Hall. "We looked at its genetic material and realised it wasn't HTLV-I, it was HTLV-II. Twenty percent of the drug users had it."His lab characterised the HTLV-II virus - another world first - and found two subtypes, which they named IIa and IIb.

Quest

The burning question was: where had the virus come from? Finding out required a bit of detective work. As he explained, the origin had to be ancient, and this helped narrow down his target. "I figured the only ancient population in North America is American Indians."

This led him on a quest to collect and analyse blood samples from North American Indians living in reservations. He discovered the Indian groups had both HTLV-IIa and IIb, but contact with outside populations made it unclear whether the virus was of Indian origin or associated with drug use.
It was time to dig deeper and find more isolated populations. Hall headed to Colombia to test among the Wayuu Indians and found they had only HTLV-IIb, no IIa at all.

His discovery sparked a rush among researchers to test other South American Indian groups, and subsequent studies confirmed that HTLV-II is a natural infection of Native Indians.

Prof Hall took things a step further. "We wanted to look at more remote populations. So I decided to go to the Amazon, but it was very difficult because you can't just walk in there." He had to secure government permission and translators, and organise transport by boat or rented Cessna planes to reach remote groups of 100-300 Indians living deep in the Amazon rainforest.

He noted that while certain populations were elegant and sophisticated, some of these groups were almost Stone Age: "Some had little infrastructure and were impoverished. Many did not live beyond ages 35-40 because of recurrent diseases such as malaria."

Prof Hall laughs about it now, but some of the journeys were hair-raising: "We had to bring our own fuel, so we'd strip the Cessnas out and put in big plastic barrels. Stuff was flying all over the place, it was really bumpy, terrifying."

Once there safely, getting permission to take blood samples could also prove tricky. At night the scientists and the translator would meet with the chief and tribesmen in the pitch blackness of a central hut to negotiate. "It could go on for hours and sometimes you wouldn't get permission until the second day. Then everyone would line up and you would draw samples and we'd take them back and process them."

When his group analysed the virus they isolated from the Amazon tribes, they found it was unusual. "Genetically was HTLV-IIa, but in terms of its protein, it was HTLV-IIb, so it was a mixture. It turned out to be HTLV-II type c, the third type."

They went on to find more type IIc in Sao Paolo among injecting drug users and women prisoners, indicating that the virus had spread out from the rainforest, probably through contact between indigenous peoples and miners.

Distinct geographical infection patterns were emerging among the Native Americans: HTLV-IIa and IIb in North America, and IIb and IIc in South America.

Tracking

Prof Hall's group used the viral distribution data to analyse Indian ancestry. "By identifying different subtypes of HTLV-II in communities in Brazil, Central America, Argentina, Colombia and North America, we were able to track the migration of their ancestors, which was very interesting."

Then it was time to delve further into the past. "We looked at the genetics of the Mongolian groups and the South American Indians and we found they had a common ancestry. They probably crossed the Bering Strait 20,000-30,000 years ago when it was a land mass." So, the researchers decided to go to Outer Mongolia.

Again, the expedition proved eventful, involving long journeys over the country in an old military helicopter. Hall's group found HTLV-I among remote peoples in Mongolia, but no HTLV-II. Not finding HTLV-II was significant, as it suggested an American origin.

As well as conducting viral anthropology studies, Prof. Hall has focused on the clinical aspects of HTLV-I, which is associated with an aggressive leukaemia.

HTLV-I infection is endemic in certain regions of the world, including south-west Japan and areas of the Caribbean and Africa. Around 20 million people are infected worldwide, yet most display no obvious short-term symptoms. However, between two and five percent eventually develop an aggressive form of leukaemia called Adult T-cell Leukaemia/Lymphoma (ATLL). It is possible that the virus has an influence on the development of this disease.

A viral regulatory protein, Tax, has been found to play a central role in the development of ATLL by upsetting the transcription of genes involved in cell cycle control, cell proliferation and cell death (apoptosis). Prof Hall's group used this knowledge to induce symptoms similar to ATLL in mice, specially bred in the lab to express the Tax protein. By observing these mice scientists are likely to find out how the disease develops in humans.

"I think it's important because even though the leukaemia only occurs in these individuals, if you can figure that leukaemia out you better understand other leukemias and other forms of cancer," explained Prof. Hall.

Bob Gallo, who discovered HTLVs-I and II recently described Prof. Hall as the world authority on HTLV II: a fitting accolade for a researcher who has literally gone to the ends of the Earth in search of the virus.