Why is it that some people infected with HIV-1 progress rapidly tofull-blown AIDS and early death, while others stay healthy for yearsbefore finally crashing?
Researchers in the field can cite at least three explanations for thisanomaly _ all of them neat, plausible and unproven:
* One hypothesis sees a viral antigenic threshold, beyond which theimmune system simply can't contain the infection.
"It's like a juggler who's given two balls to juggle for starters,"analogized molecular virologist Steven Wolinsky. "He can handlethem, then three, four and more. But as the number of objects he hasto keep in the air increases, at some point they all come crashingdown."
Wolinsky, who is on the faculty at Northwestern University, inChicago, explained this first hypothesis as "predicting that at a timewhen a patient's disease progresses, so does the number of antigenicvariants of the infecting virus."
Clinicians measure disease progression by the loss of the cellularimmune system's helper T cells, which carry CD4 glycoproteins ontheir surface. These CD4s are the bulls' eyes targeted by invadingHIV-1
* The second theory hypothesizes that the body's CD4 T lymphocytepopulation declines as a consequence of the cellular immuneresponse.
"This," Wolinsky explained, "would predict that as the diseaseprogresses, cytotoxic T lymphocytes [CTL] increase. Those killer Tcells target the HIV-infected helper cells, and remove them from thebody."
Disease progression kicks in, this hypothesis explains, when there areno more T cells for the CTLs to destroy. The more vigorous the CTLcounter-attack, the more virus-harboring CD4 T cells it would kill,until none were left to remove.
"This implies," Wolinsky said, "that those CTLs exert a pathogeniceffect. Rather than helping, they hinder the immune response, bywiping out the CD4 T cell defense."
* A third hypothesis puts the monkey on the back of the virus, ratherthan on the overzealous CTLs. "This postulates that the underlyingviral infection is mediating the host-cell interaction by whatevermechanism _ direct killing or apoptosis [programmed cell death],"Wolinsky said.
Six Infected Men Model AIDS' Natural History
"To critically evaluate these three hypotheses," Wolinsky toldBioWorld Today, "we have studied six homosexual men at risk ofHIV-1 infection." They were among 4,877 men enrolled in anongoing four-center AIDS study begun in 1984, and funded by theNational Institute of Allergy and Infectious Diseases (NIAID).
"We had this repository of stored blood plasma from people whocould be divided up into different rates of progression to disease, sowe were able to choose our six probands on the basis of their rate ofCD4 T cell decline, following seroconversion [primary infection]."
Wolinsky is first author of a progress report on their study in today'sScience, dated April 26, 1996. Its title: "Adaptive evolution of humanimmunodeficiency virus type 1 during the natural course ofinfection."
Summarizing the disease course in the six men studied, he said: "Twoof the six had progressed rapidly to death, within 36 and 42 monthsrespectively, following seroconversion. Another two had a longersurvival, but with progressive CD4 T cell loss. Of the last two men,one who had a stable CD4 count above 500, was lost to follow-up;the other maintains a relatively high count above 1,200."
The first step in the study was to measure the viral burden in theplasma against the CD4 T cell count over time. The amount of freevirus circulating in the blood, Wolinsky said, "proved to be apredictive value for determining disease outcome."
Next, the investigators sequenced segments of the viral envelopegene at sequential time points in each man studied, and analyzed thevariant epitopes as the virus mutated within the individual. In the twowho died after rapid progression they found "a very limited variation.In contrast, the people who had a slower disease course, or failed toprogress at all, had marked variations."
"This counter-intuitive finding," Wolinsky observed, "showed thatwe lacked evidence to support an antigen-diversity model; thatprogression was not related to diversity."
They then went on to examine the humoral [antibody] and cellular [Tcell] immune response roles in HIV-1 infection.
In none of the six patients could they find any connection betweenantibody responses and disease progression. "When we looked at thecell-mediated effects," Wolinsky said, "we found a more vigorousCTL in people who did not progress, whereas those who rapidlyprogressed had practically undetectable CTLs."
So he and his co-authors reported "no evidence that CTLs wereresponsible for a pathogenic effect, but were basically good for thehost rather than bad."
Wolinsky and his team then turned to their concept of adaptiveevolution:
"The half-life of the virus in the circulation," he observed, "isapproximately six hours; in infected cells, 1.2 days. Every time itreplicates, it's mutating. Yet, despite this rapid turnover and highmutation rate, we see no viral change over time in the rapidlyprogressing patients."
He continued: "One may postulate that it's a very fit variant of virus,able to handle itself well in its environment, and free of selectionpressures. There's nothing to disturb its equilibrium; it has no need tochange."
Wolinsky made the point: "That's what we see in these rapidprogressors _ and that's what we see in sharks, over the last 200million years."
He explained: "Sharks haven't changed over time. They're veryefficient killing machines, well adapted to their environment. HIV inthat kind of situation, where there are no pressures on it to change,will not show genetic variation.
"In the other situation," he added, "where the virus is under selectiveconstraints, we found that the immune system generated thesepressures as a function of the six mens' individually varied,genetically endowed expression of HLA antigens _ which bring theviral antigens to the notice of the immune system."
"In effect," Wolinsky summed up, "those people who don't progressto the disease are showing variation; the virus is changing over time.What this means, basically, is Darwinian, or adaptive, evolution."
One Up On Darwin
"The beauty of this Science paper," he went on, "is that we are ableto determine what the selective pressures on HIV-1 are, which is theadvantage we have over Darwin."
Immunologist Richard Koup, of the Aaron Diamond AIDS ResearchCenter in New York City, is the paper's senior author. He toldBioWorld Today that he, Wolinsky and their associates have begun alarger repeat study of 30 patient samples rather than six.
An editorial in Science accompanying their paper concluded: "HIV-1may be best contained by combining immunotherapy with antiviraldrugs."
Koup commented on that commentary: "When you look at howpotent and how elegant some of our anti-retroviral chemotherapiesnow are, and how wimpy, under-developed and unknown ourimmunotherapies are, I would say: `Let's punch ahead with theantivirals.'" n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.