By David N. Leff
In gang warfare, the street word ¿shiv¿ means a knife or pointed blade used as a lethal weapon.
In current AIDS research, ¿SHIV¿ stands for ¿simian-human immunodeficiency virus.¿ This viral hybrid is one of the latest tools in the effort to design more efficacious vaccines and antiviral drugs as weapons against the AIDS epidemic.
SHIV virologist Janet Harouse perceives a link of sorts between shiv and SHIV. ¿Basically, what we¿ve done,¿ she pointed out, ¿is make a more pathogenic AIDS virus. These SHIVs that we¿re using infect monkeys, but no one knows what they would do in humans.¿
Harouse, a research scientist at the Aaron Diamond AIDS Research Center in New York, is first author of a paper in today¿s issue of Science, dated April 30, 1999. Its title is: ¿Distinct pathogenic sequelae in rhesus macaques infected with CCR5 or CXCR4 utilizing SHIVs.¿
¿There are two significant parts to this paper,¿ Harouse told BioWorld Today. ¿The first one is a CCR5-using SHIV. That¿s important for preclinical evaluation of vaccines and therapeutics. So that¿s one of the main findings of the paper.
¿The second,¿ she went on, ¿reports the differences in pathogenesis between the X4 and the R5 viruses. I think that¿s also important in vaccine development, because it gives us a better handle on what we need to do, or where we need to look in the human body, to address the issue of vaccine efficacy.¿
SHIVs of two persuasions have emerged from AIDS research labs of late for infecting primate models of AIDS. ¿Our group and several others,¿ Harouse recalled, ¿have published SHIV hybrids of simian and human immunodeficiency viruses. But unfortunately, no one had been able to get the R5 SHIV. We have an X4 and an R5, so it enables comparison of the two, which adds to understanding the viral pathogenesis. The ability to have made an R5 SHIV is really the novel aspect of this work.¿
In order to break and enter its target cell ¿ a CD4-positive T lymphocyte, a macrophage or an intestinal epithelial cell ¿ an AIDS virus resorts to cofactors, notably CCR5 and CXCR4, to serve as accomplices in fusing with the target¿s outer membrane. (See BioWorld Today, May 13, 1996, p. 1, and June 21, 1996, p. 1.)
¿The viruses that are using R5,¿ Harouse explained, ¿are very prominent early on in infection. As the patient progresses,¿ she continued, ¿you begin to see the emergence of the X4 viruses in about 50 to 60 percent of the cases. And with that emergence, you also begin to see the onset of clinical AIDS.
¿So it appears that this phenotypic switch from R5 to X4,¿ Harouse pointed out, ¿is one of the underlying mechanisms of disease development. How this switch occurs is totally a matter of conjecture at this point in time. And the ability of the virus to use either X4 or R5 as its cofactor comes from a different viral epitope. It hasn¿t been determined which epitopes are responsible for each one.
¿The purpose of cross-breeding simian and human viruses,¿ she explained, ¿is because, for pathogenesis work and vaccine development, animal models are critical. That¿s how most vaccines have been developed. The simian virus does not use CXCR4, but it does use CCR5. The part of the viral envelope that binds CCR5 is very different between the animal and the human viruses. So by placing the human envelope within the SIV virus we now have created a system that¿s more similar to the human condition.¿
Harouse made the point that, ¿There¿s a large area of interest now for developing CCR5 blockers. So if you want to go in and look at drugs or vaccines that are targeted against the envelope protein, a primate infected with this SHIV is probably a better and more faithful model.¿
She and her co-authors constructed two SHIV strains, by recombinant technology. After in vitro testing, they injected them intravenously into rhesus macaque monkeys. Then they monitored disease progression in the animals.
Each version produced its own distinct pathological effect. Both animal groups experienced comparable levels of viral replication, but the two SHIVs differed sharply in their impact on T cells. Monkeys infected with the R5 SHIV had a rapid, dramatic loss of intestinal T cells, followed by a gradual decline of peripheral blood T cells and little further intestinal loss.
These results confirmed their performance as sophisticated animal models for testing AIDS vaccines and therapeutics, the Science paper suggested.
To date, a veritable zoo of primate models has been developed ¿ each with built-in shortcomings ¿ from infecting macaques with SIV to infecting macaques and chimpanzees with HIV-1, to macaques and baboons with HIV-2.
¿One of the more important discoveries that also came out of the Aaron Diamond,¿ Harouse recounted, ¿was that individuals who have a certain deletion in their CCR5 gene are, for the most part, resistant to sexual transmission of HIV. The study of those people showed that, if you can block the entry of the virus, what happens is they¿re highly resistant to high-risk sexual infection and to AIDS, but still susceptible to intravenous transfer of the virus, and hence to the disease.
¿There are long-term non-progressors, and also individuals who have repeat exposures,¿ Harouse continued, ¿and do not convert, do not come down. There clearly is more than one reason why this occurs. One of the reasons is that CCR5 mutation, which occurs in about one in 100 Caucasians.
¿The data,¿ she pointed out, ¿show that blocking transmission, blocking viral entry, is a big protector. And that¿s what a lot of AIDS vaccines are targeting against.¿
Tailoring Anti-Transmission To Global Mores
She made the point that in most of the world, unlike the U.S., HIV spreads, and AIDS ensues, because the virus enters by crossing mucous membranes rather than by infecting the bloodstream, as with donor transfusions or dirty needles.
¿Sexual transmission is the major mode of spread in the world today,¿ she observed, ¿so we are now looking at the ability of the virus to cross the mucosal membrane. We have established sexual transmission models in our primates. So these are the areas we are starting to go more into, trying to develop a model that would be better or more faithful for the eventual aim of vaccine trials. And also, for more perspective, looking at pathogenesis ¿ where the virus is going, and why different HIV strains may go to different places in the body ¿ the gut, the brain, the thymus, the blood.¿ n