The Gambia, once infamous as a focus of endemic sleeping sickness(Trypanosoma brucei gambiense) is today the locus of a unique questfor an AIDS vaccine.
What makes this tiny West African country a special site for seekingimmunity against HIV is the fact that one third of its population(which totals about 900,000) carries a particular molecule of thehuman lymphocyte antigen (HLA) immune system _ number B35.In western countries generally, molecular immunologist SarahRowland-Jones, of Oxford's Radcliffe Hospital, told BioWorldToday, "B35 is present in only one-fifth of the population." Shedirects a research project on AIDS in The Gambia, sponsored byBritain's Medical Research Council (MRC).
In the human immune system, two kinds of white blood cells fightoff invading pathogens, such as viruses. B lymphocytes churn outantibodies that hunt down intruding antigens, and pin them down fordestruction by the complement system. Cytotoxic T lymphocytes, astheir name implies, seek out and kill outright cells infected byviruses or other pathogenic microbes.
"What T cells see," Rowland-Jones said, "are short fragments ofviral protein that have been broken down in the cell. Then they cometo the T cell surface on the HLA histocompatibility molecule."
B35 Molecules Point Out HIV Antigens To Killer T Cells
She explained: "The kind of HLA molecules that you have determinethe kind of peptide that your cytotoxic T cells will respond to. AndB35 is just a particular one of those HLA molecules that happens tobe very very common in West Africa." She added, "We had to startfrom scratch, really, because most of the work that we have donepreviously was in British populations, whereas the West Africanshave quite different tissue types."
She continued, "We were trying to demonstrate whether thecytotoxic T cells against HIV could be found in people exposed tothe virus, but not actually infected. It would be a sign that they hadmet replicating virus, but managed to fight it off in some way."
Rowland-Jones is first author of a paper in the premier issue ofNature's spin-off journal, Nature Medicine. Its title: "HIV-specificcytotoxic T cells in HIV-exposed but uninfected Gambian women."
The women were prostitutes, who by definition had been repeatedlyexposed to HIV infection, yet remained free of disease or infection,as evidenced by being seronegative _ having no antibodies to HIVin their blood.
"The method that we used," Rowland-Jones said, "was to take cellsfrom six uninfected prostitutes and culture them directly withpeptides representing the fragments of virus that toxic T cellsrespond to. We found that in three of those women we could detectcytotoxic T cell activity against a whole panel of peptides. But inmore than 20 control patients, who also had HLA type B35, but noHIV exposure, we didn't find any T cell activity."
This finding led Rowland-Jones and her co-authors to conclude thatthe cytotoxic T cell activity of the three repeatedly exposedprostitutes "may represent protective immunity against HIVinfection."
At this point, she pointed out another "interesting" singularity ofGambia's population, which makes their small sliver of a country anatural laboratory for AIDS vaccine research: "Both HIV-1 andHIV-2 are circulating in The Gambia. People were probably exposedto HIV-2 first, because that had been around for a few years longer."
She and her team found that "if people were infected with HIV-1,their T cells also recognized the corresponding region of HIV-2, andvice-versa.." Such cross-reactivity, she observed, "is fairly unusual."
"HIV-2 does cause AIDS in West Africa," she went on, "but it mighttake 10 or 20 years to do it in an individual. So in some ways HIV-2behaves like an attenuated virus."
This recalls the historic cross-reactivity between the virulentsmallpox variola and avirulent cowpox vaccinia viruses, which ledliterally to vaccination.
AIDS Vaccine Research, Development Proceed In Parallel
Back in The Gambia a few weeks ago, Rowland-Jones found thethree women "still have cytotoxic T cell activity that we can detect,but they remain seronegative, and we can't grow virus in them ordetect virus by PCR [polymerase chain reaction] either."
With a new five-year grant from MRC, Rowland-Jones plans to"extend the studies to more Gambian women, to see whether those inwhom we can find the cytotoxic T cell activity are protected againstHIV on a long-term basis."
The prostitutes who check in regularly at the MRC-sponsored clinicreceive free medical care in return for contributing blood to theresearch project. "These women," Rowland-Jones observed, "duringthe last few years have all had either gonorrhea or syphilis orchlamidia, so we're very sure they've not been using condoms, atleast not on a regular basis."
While she and her team continue over the next five years to researchthe source and durability of the apparent immunity in these women,others within her group "are working in monkeys on vaccines thatwould stimulate cytotoxic T cells _ predominantly a T cell ratherthan an antibody response. They feel," she said, "that they are gettingsome success in protecting monkeys with this kind of vaccine. So Ithink we would expect these findings, already going on in parallel, tobe translated into vaccine trials within a few years."
Immunologist Bruce Walker at Harvard Medical School andMassachusetts General Hospital is well acquainted with Rowland-Jones and her MRC project in The Gambia. "Our lab," Walker toldBioWorld Today, "was actually the first, in 1987, to describe thissort of immune response in infected people."
The reported ability of the Gambian prostitutes to make immuneresponse to the virus, Walker added, "raises the question as towhether they may have become infected and cleared the virus, orwhether they got a subinfectious dose, which generated the immuneresponse."
He expressed the hope that "the presence of this response wouldprevent them from becoming infected in the future, but there's reallyno evidence thus far to indicate that that is the case."
Hence, Walker suggests, "one would have to interpret the veryinteresting Gambian finding with caution at this point." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.