WASHINGTON -- Vaccine researchers may be targeting thewrong type of AIDS virus, according to a report given at TheFirst National Conference on Human Retroviruses and RelatedInfections. Two other reports had implications for augmentingimmune response to HIV.
The four-day conference, which began here on Monday, wasco-sponsored by the National Foundation for InfectiousDiseases and the American Society for Microbiology, incollaboration with the National Institutes of Health and theCenters for Disease Control.
In studies of 20 acute seroconverters, David Ho of the AaronDiamond AIDS Research Center in New York found that 19 ofthe patients carried non-syncytial viruses, even though four oftheir disease-transmitting partners had syncytial virusinfections. In fact, the populations of virus followingseroconversion are extremely homogeneous sequencescompared with those in chronically infected individuals, saidHo.
The transmitted viruses matched those in the infectingpartner's semen better than those from the rest of the body,but the transmitted variant is a minor variant even in thesemen, Ho said. This research was performed by Tuofu Zhu, apost-doctoral researcher in Ho's lab.
Vaccines are being developed against syncytial viruses, said Ho.But the transmitted virus is non-syncytial and has a uniformphenotype, and that should be the vaccine's target, he said.
CD8-Positive T LymphocytesVaccines probably should also boost virus-specific CD8-positivecytotoxic T lymphocytes (CTLs), but not CD4's, said RichardKoup, also of the Aaron Diamond Center. The former, he said,appear to be more important in the immune system's earlyresponse to HIV. They are associated with clearance of viremia,and a fast progression to AIDS may be in part the result oftheir absence.
Among the five patients Koup studied, four had developeddetectable CTL precursors within three weeks following acuteseroconversion. (The fifth had been measured prior toseroconversion, and then had no detectable precursors.) Threeto six months later, all patients had CTLs. Conversely, patients'levels of neutralizing antibodies were either non-existent orvery low.Koup performed detailed examinations of two patients' immuneresponses. Shortly after seroconversion, patient V, a slowprogresser, had developed CTLs to gag, pol and env. But at thissame stage, patient R, a rapid progresser, had no detectableprecursors against the three epitopes. At 178 days he still hadnone against gag.
"This is very basic research to dissect initial immune responseto show how rapidly the virus can escape from immuneresponse," Koup told BioWorld. "In acute infection it's the CD8-positive CTL response and not the CD4-positive CTL which istemporally associated with clearance of viremia. Therefore, onecould conclude the CD8-positive class-one restricted response isthe important one to stimulate with the vaccine.
Virion-Associated RNAOther differences between rapid and slow progressers may alsobe relevant to treatment for HIV, said Jaap Goudsmit of theUniversity of Amsterdam. In slow progressers, virion-associated RNA declines steadily for several years after itpeaks within a few weeks of seroconversion. Among rapidprogressers, the early peak is followed by a slight dip and thena plateau.
In a study of 109 male seroconverters, 29 of whom developedAIDS, the level of viral RNA peaked around 10 to the fifth RNAmolecules per milligram blood serum, and wasindistinguishable between the two groups, said Goudsmit.
Three years after seroconversion, while patients were still freeof symptoms, the amount of HIV RNA had remained stable inthe progressers but had dropped quite significantly in the non-progressers.
Goudsmit also compared 300 base pairs of env, including thev3 loop, among the study subjects. "At seroconversion, you seeno genetic divergence between progressers and non-progressers," he said.
"We think there is some kind of interference event in theslower progressers," said Goudsmit. "We think this has majorimplications" because it might be possible to distinguishbetween the two groups very early in the asymptomatic stage.Goudsmit believes that the differences between the two groupsmay have determined clinical outcomes in trials of AZT.
-- David C. Holzman Washington Editor
(c) 1997 American Health Consultants. All rights reserved.