HIV attaches to cell/2

It would not be a shock to me if a vaccine were successful in five years. Trying to get a foothold
The excitement reflects the importance of preventing HIV infection rather than treating it. The emphasis on entering the cell reflects the fact that viruses are impotent until they sneak inside a cell and commandeer the cell's machinery for their own devious purposes. But once they do, they're hard to attack, as they're located in the cell's nucleus, behind two protective membranes.
Unlike bacteria, viruses are not really alive, but are a set of instructions -- made of either DNA or, as in the case of HIV, RNA -- looking for a home base to execute those instructions. Incidentally, that "non-living" status is another reason viruses are hard to attack, since they have fewer metabolic targets than bacteria.

Why does HIV need two receptors?
Good question. The picture of HIV's entry into the cell is getting more complicated with the old receptor, CD4, now being seen as one of two crucial steps. Yet the need for two receptors "is not completely understood," Springer says. Apparently, HIV "undergoes a conformational change when it binds to CD4, and it may have to do with evading the immune response."

This diagram illustrates the theory of the role of the second receptor.
1. CD4 binding
2. Conformational change
3. CCR-5 recruitment
4. membrane insertion
5. membrane fusion
Illustration ©Dr. A.J.Cann, University of Leicester, Department of Microbiology & Immunology.

And it would not be a shock to me if there was no progress in five years.
diagram showing the second receptor theory
Perhaps, he says, HIV only exposes certain parts of its coat when they are needed. The system -- still speculative, we must add -- may resemble a two-step password system for computer security. Only those who had the first password would be asked the second password. That system would protect the second password from prying eyes of people lurking near the first entrance.
Once we've started speculating, it's kind of hard to stop. I was wondering where is this chemokine research leading?
The excitement about chemokines is not just the rapture of scientists who have unravelled a knotty problem. It's also the gathering excitement that chemokines offer several new ways to attack and possibly defeat HIV. The reason is this: one of the two chemokine receptors seems like some kind of spare part.
"We've shown that the CXCR4 [a receptor for alpha chemokines] are active in guiding leukocytes through the body," says Springer. The receptor is also widely distributed, and is seen on crucial cells that form blood cells. "Indeed, mice that have no gene for CXCR4 die at birth," he adds.
In contrast, he adds, "People who are missing CCR5 [a receptor for beta chemokines like RANTES] look perfectly healthy."
That fact has sparked a search for possible applications for chemokines in the battle against AIDS in at least 14 drug companies and research labs (see "Exploiting the HIV-Chemokine Nexus" in the bibliography).

Chemokine-like drugs could prevent HIV from attaching to T-cells, thus occupying receptors and blocking HIV from using them. Gallo intimates that at least one drug giant is developing a chemical "that will target HIV by mimicking the chemokines." And LeukoSite, a Massachusetts firm, has started developing antibiodies to CCR5 with the intention of testing them on monkeys and people.

The body could be convinced -- with drugs or genetic engineering -- to create higher levels of beta chemokines. The goal would be for the body to perform step #1.

With genetic engineering, T-cells could be created without the deadly CCR5 receptors.

Chemokines could be used to assess the status of infection. During the initial period of HIV infection, which can last 10 years, the patient has no or few symptoms. But when the disease AIDS appears, the immune response fails and opportunistic infections eventually kill the patient.
It turns out that when AIDS appears, HIV changes, and that the more deadly form cannot be blocked by chemokines, Gallo says. "The virus that just enters a patient is sensitive to [can be blocked by] chemokine," while the cell-killing kind of HIV that develops later in the infection can not. Thus by measuring whether beta chemokines can block HIV, doctors might be able to determine when the virus turned deadly.

Finally, Gallo says the chemokine research could be a shot in the arm for AIDS vaccine development. The field has had disappointing results, to put it mildly, but Gallo insists that, given the worldwide extent of the epidemic, prevention, not cure, should be the real goal in AIDS research.
However, one immunologist suggested that beta chemokines would have to be taken constantly, making it a preventative or a treatment, not a vaccine. And Gallo is not claiming an inside track on vaccine research, only that it's critically important. "It would not be a shock to me if a vaccine were successful in five years. And it would not be a shock to me if there was no progress in five years."

Update
2 JULY 1998. In the past two years, the HIV co-receptor issue has gotten considerably murkier. More than 12 co-receptors have been located, and it's unclear what their role is. Since some of the new-found receptors appear on specific tissues, they may explain why the disease progresses as it does over the course of the infection. If HIV can enter through a variety of co-receptors, then the chance for effectively blocking any given co-receptor would seem diminished. Yet because people with defective CCR5 co-receptors are immune to HIV, that molecule remains a promising target for drug treatment. (See "AIDS Researchers Negotiate..." in the bibliography)

.
One place we've definitely seen progress is in the next stage of HIV's invasion-- when it copies its RNA to make viral DNA.

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This diagram illustrates the theory of the role of the second receptor. 1. CD4 binding 2. Conformational change 3. CCR-5 recruitment 4. membrane insertion 5. membrane fusion Illustration ©Dr. A.J.Cann, University of Leicester, Department of Microbiology & Immunology.	Perhaps, he says, HIV only exposes certain parts of its coat when they are needed. The system -- still speculative, we must add -- may resemble a two-step password system for computer security. Only those who had the first password would be asked the second password. That system would protect the second password from prying eyes of people lurking near the first entrance. Once we've started speculating, it's kind of hard to stop. I was wondering where is this chemokine research leading? The excitement about chemokines is not just the rapture of scientists who have unravelled a knotty problem. It's also the gathering excitement that chemokines offer several new ways to attack and possibly defeat HIV. The reason is this: one of the two chemokine receptors seems like some kind of spare part. "We've shown that the CXCR4 [a receptor for alpha chemokines] are active in guiding leukocytes through the body," says Springer. The receptor is also widely distributed, and is seen on crucial cells that form blood cells. "Indeed, mice that have no gene for CXCR4 die at birth," he adds. In contrast, he adds, "People who are missing CCR5 [a receptor for beta chemokines like RANTES] look perfectly healthy." That fact has sparked a search for possible applications for chemokines in the battle against AIDS in at least 14 drug companies and research labs (see "Exploiting the HIV-Chemokine Nexus" in the bibliography). Chemokine-like drugs could prevent HIV from attaching to T-cells, thus occupying receptors and blocking HIV from using them. Gallo intimates that at least one drug giant is developing a chemical "that will target HIV by mimicking the chemokines." And LeukoSite, a Massachusetts firm, has started developing antibiodies to CCR5 with the intention of testing them on monkeys and people. The body could be convinced -- with drugs or genetic engineering -- to create higher levels of beta chemokines. The goal would be for the body to perform step #1. With genetic engineering, T-cells could be created without the deadly CCR5 receptors. Chemokines could be used to assess the status of infection. During the initial period of HIV infection, which can last 10 years, the patient has no or few symptoms. But when the disease AIDS appears, the immune response fails and opportunistic infections eventually kill the patient. It turns out that when AIDS appears, HIV changes, and that the more deadly form cannot be blocked by chemokines, Gallo says. "The virus that just enters a patient is sensitive to [can be blocked by] chemokine," while the cell-killing kind of HIV that develops later in the infection can not. Thus by measuring whether beta chemokines can block HIV, doctors might be able to determine when the virus turned deadly. Finally, Gallo says the chemokine research could be a shot in the arm for AIDS vaccine development. The field has had disappointing results, to put it mildly, but Gallo insists that, given the worldwide extent of the epidemic, prevention, not cure, should be the real goal in AIDS research. However, one immunologist suggested that beta chemokines would have to be taken constantly, making it a preventative or a treatment, not a vaccine. And Gallo is not claiming an inside track on vaccine research, only that it's critically important. "It would not be a shock to me if a vaccine were successful in five years. And it would not be a shock to me if there was no progress in five years."

		Update 2 JULY 1998. In the past two years, the HIV co-receptor issue has gotten considerably murkier. More than 12 co-receptors have been located, and it's unclear what their role is. Since some of the new-found receptors appear on specific tissues, they may explain why the disease progresses as it does over the course of the infection. If HIV can enter through a variety of co-receptors, then the chance for effectively blocking any given co-receptor would seem diminished. Yet because people with defective CCR5 co-receptors are immune to HIV, that molecule remains a promising target for drug treatment. (See "AIDS Researchers Negotiate..." in the bibliography)

	. One place we've definitely seen progress is in the next stage of HIV's invasion-- when it copies its RNA to make viral DNA.