What if AIDS could be made, as the saying goes, "no worse than abad cold?" That far-out notion is, in a conceptual way, motivating ahusband-and-wife team at Rutgers University, in Piscataway, N.J.
Gail and Edward Arnold, she a molecular biologist-cum-virologist,he an X-ray crystallographer, jointly incubated the idea ofconstructing an AIDS vaccine by piggybacking a potent HIVimmunogen onto the surface of a rhinovirus, cause of the commoncold. Any rhinitis sufferer will testify that the cold virus packs apretty powerful antigenic attractant itself.
They document their proof-of-concept in this month's Virology undera title that spells out their experiments to date: "Chimeras from ahuman rhinovirus 14-human immunodeficiency virus type 1 (HIV-1)V3 loop seroprevalence library induce neutralizing responses againstHIV-1."
HIV's V3 loop, Gail Arnold (the paper's principal author) toldBioWorld Today, "is the part of the viral surface antigen, gp120, thatgives the dominant immune response of the entire HIV-1 virion."
Using tricks of genetic engineering on which Rutgers has patentspending, she selected and cloned V3's most immunogenic portions,and attached them to each of the 60 geometric surfaces that pave therhinoviral virion's outer coat. Thus the immune system of a bodyvaccinated with this chimeric, antigenic duo _ disembodied HIVepitope hitchhiking on harmless cold virus _ would "see" both, andgenerate antibodies to "remember" the AIDS antigen in future time ofneed.
"Our goal," Gail said, "is to mimic the HIV immunogen, both insequence terms and in structure. Instead of just encoding thesequence of one viral strain," she added, "and developing immunityagainst that one strain, we are making composite strains."
Fifteen Guinea Pigs To Prove The Concept
These reflect, she said, the HIV-1 amino-acid variants "that havebeen characterized for a given part of the world, or maybe the wholeworld, or whatever."
Fifteen guinea pigs took part in the Arnold's first in vivo test of theputative vaccine. Not that these small rodents can contract AIDS, oreven catch cold, but their immune systems do raise antibodies againstinvading epitopes.
Three animals got injections of each of five composite strains. "Afterthey had had time enough to develop antibodies," Gail said, "we tooktheir serum and asked whether their antibodies could block infectionof HIV-1 in human cell culture." Four of the five recombinant virusescould.
"We assume that means," she explained, "that those parts of the V3loop must look like they do in the context of HIV. It must be areasonably good mimic of the HIV loop. So it's an easy way toscreen for what might be a good immunogen."
Edward, she said, "is now looking at the structure of our most potentchimeric immunogen."
Unlike guinea pigs but like humans, chimpanzees can be infectedwith the AIDS virus, which is why they are the indispensablepreclinical animal model. "We've actually done an experiment," Gailrecounted, "injecting a chimp with wild-type rhinovirus to prepare usfor infecting one with a couple of our chimeric viruses. We're hopingto do the analogous trial this fall."
Unique? Yes; Protective? Remains to be Seen
The Rutgers couple now have a four-year grant from the AIDSvaccine program at the National Institute of Allergy and InfectiousDiseases, to pursue theiruncommon-cold vaccine.
Virologist Alan Schultz is chief of that program's preclinical researchbranch, and provided those first two preliminary chimps.
Schultz told BioWorld Today: "One of the disadvantages of peptidevaccines is that they do not represent the conformation that a peptidesequence has in the pathogenic organism. The Arnolds have come upwith a unique way of designing and selecting for immunogenicconstructs, these rhinoviral constructs, in which the HIV peptideshave a stable conformation."
He added, "And if they have done a sufficiently clever selection, thatshould mimic what you find in HIV. So at that stage it's atechnological breakthrough _ just a lovely, lovely piece of work."
But Schultz tempered this evaluation by observing, "Now, whether ornot having three-dimensional configuration, whether or not gettingV3 and maybe another portion of gp120 which has something to dowith neutralization, is in and of itself sufficient to make a vaccine isof course entirely unknown. So that's the `on-the-other-hand' part ofit."
Another unknown, he pointed out, is that "if you are going tovaccinate people by spraying the rhinovirus in their nose, what withthe mucosal immune system, you are likely to get immune responsesrectally and vaginally. It remains to be seen if these would be relevantto protection."
Apropos protection, Gail Arnold concluded, "Our expectation is thatthis kind of vaccine would certainly be good prophylactically. Ourhope is that it could be therapeutic as well, for an HIV-infectedperson who is early enough along so he can still mount a goodimmune response." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.