Monkeys - subhuman primates - come in different sizes, shapes, lifestyles and homelands, but they share one commonality. Monkeys seem to have been born already resistant to infection by the human immunodeficiency virus.
Actually, they and other primate species were born that way - immune against the AIDS virus. This may come as a boon to those wild African, Asian and South American animals, many of whom make a good living acting as people-aping pets. But their indifference to HIV infection makes them useless as animal models for development of vaccines against the virus.
That leaves the field wide open to the bulkier, costlier chimpanzees - ostensible progenitors of HIV - which can contract the infection. But a chimp's price tag puts it out of reach in the quantities that would be needed to develop and test an effective anti-AIDS vaccine for human use.
Molecular virologist Paul Bieniasz presents a putative way around this impasse, by turning those primates' HIV-proofing inhibition to vaccine-designing advantage. A staff scientist at the Rockefeller University-affiliated Aaron Diamond AIDS Research Center in New York, his laboratory focuses on interactions between the virus and its target host cell.
Bieniasz is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), released online July 29, 2002. Its title: "Cellular inhibitors with Fv1-like activity restrict human and simian immunodeficiency virus tropism [i.e., ability to infect]."
A Zoofull Of Primates Unanimously Block HIV
"The central finding in our PNAS paper," Bieniasz told BioWorld Today," is that cells from primate species can express an inhibitor that blocks infection by HIV - and sometimes by SIV, a related simian immunodeficiency virus. We now know," he continued, "that this inhibitor targets the capsid protein of the HIV virus, and goes to work after the virus has entered the cell but before it has integrated its genome into that target. The spectrum of activity of the inhibitor seems to depend on what primate species the target cell is derived from. So we have tested rhesus macaques vs. African green monkeys vs. owl monkeys vs. squirrel monkeys.
"Two kinds of HIV affect humans," Bieniasz went on. "The one that's spread most widely, globally, is HIV-1. That most likely originated in chimpanzees. Then there's HIV-2, which is largely confined to West Africa. It most likely came from sooty mangabey monkeys. The virus generally used in vaccine research is from rhesus macaque monkeys. We call it SIVmac, which probably originated in sooty mangabeys, and is fairly closely related to HIV-2. Until this finding," Bieniasz pointed out, "we simply didn't know that such an activity targeted against the human immunodeficiency virus and related viruses existed at all.
"All our experiments have been done in tissue culture," Bieniasz recounted, "using cell lines derived from these monkey species. What we did was infect them with either HIV or SIV. We used viruses that we'd engineered to carry a gene expressing green fluorescent protein, so we could easily measure the number of cells that were infected. And what we found was a very dramatic difference between species in their relative susceptibility to the human and simian immunodeficiency viruses. We did a kind of in vitro breeding experiment, where we took monkey cells, which are resistant, and human cells, which are sensitive, and fused them together. What we got was a resistant chimeric cell. It was formal demonstration that there's an inhibitor present in the monkey cells rather than there being a missing factor that's required.
"I think the implications are really twofold," Bieniasz suggested. "First, we know for instance that rhesus macaque monkeys are resistant to infection by HIV-1. And this inhibitory activity is one of the mechanisms that prevents rhesus macaques from being infected. Now because we know which part of the virus its inhibitor targets, it's at least possible that we could change HIV-1 in such a way that it would be able to infect rhesus macaques.
"Currently, all vaccine research is done primarily in macaques, using SIV rather than HIV-1," Bieniasz reiterated. "It's kind of a leap of faith that vaccines that work in the SIV system would be translatable to the HIV systems used in humans.
"Now if we are able to make a variant of HIV-1 that can infect rhesus macaques, that I think would revolutionize vaccine research. Because then we could test the actual immunogens that would be going into people. We could test them in animals first. So that's one major potential practical application of this research. We're working toward it very actively," he said. "What we are doing is trying to alter the capsid protein of HIV-1, so we know that the inhibitor targets the capsid. The viral capsid," he explained, "is part of gag, which is a polyprotein. It's cleaved by the viral protease into several subunits, one of which is the capsid. HIV has this cone-shaped core inside it. That capsid protein is the structure that the primates' inhibitory activity targets. We're trying to make subtle alterations in that capsid protein so that the AIDS virus can then infect monkey cells."
Main Project: Rejigger HIV To Repel Inhibitors
"We're tackling this job with a combination of random mutagenesis and a few guesses as to where we think the target site might be. What we're showing is an interaction between target cell and capsid, which is actually independent of the host's immune system. This activity," Bieniasz concluded, "could dramatically influence the ability of the virus to jump from one species to another."
Bieniasz isn't the only molecular virologist to discover HIV inhibitors in monkey cells. A companion paper in the same issue of PNAS is titled: "Restriction of lentivirus in monkeys." Its senior author is molecular virologist Greg Towers at Columbia University in New York. "I think both our papers are very similar," Towers told BioWorld Today, "but his is more detailed than mine."
Besides the usual primate suspects, Towers added: "Bieniasz's message is the same as ours, except for the rabbit cells we tested as well. One extra point in my paper," he concluded, "is we've shown that rabbit cells probably express a factor able to block HIV."