This article is written to explaine a very technical subject to an non-technical audience. I have suggested possible topic sentence in green. They are not perfect but if you read just the topic sentences you can get the flow of the argument; see those sentences at the end.

From issue of The Chronicle of Higher Education dated May 28, 1999

POINT OF VIEW

Can We Make an AIDS Vaccine?

By DAVID BALTIMORE

The news media are full of stories about the commitment of both the federal government and private companies to the development of a vaccine for AIDS. But do most people understand the scientific challenges involved in producing such a vaccine? Are their expectations too great?

Unquestionably, no more important goal exists in medical research today than the development of an AIDS vaccine. Last year, AIDS, caused by H.I.V., was the infectious disease that killed the most people around the world, and the epidemic is not abating. The developed countries of North America and Western Europe have seen a reduction in the rates of infection within their borders, both because of changes in their citizens' behavior and because a large percentage of people in those countries who are at risk of AIDS are already infected. But the virus is spreading at a phenomenal rate in Asia and Africa, and only a vaccine will stop it.

Can we make an AIDS vaccine? One might think that, because we have produced vaccines against most human viral infections, of course we can make one against AIDS. But H.I.V. is a new story. History is a poor guide when it comes to this killer.

Our immune system can effectively interfere with the multiplication of any virus that spreads solely among humans. Few people have died of the common cold, or of the measles or the mumps. The majority of people infected by even such potential killers as polio and smallpox -- now eliminated by vaccines -- survived, thanks to their immune systems. Viruses that do kill most of their human victims spread chiefly in animals but occasionally infect our species. Those viruses, which include Ebola and the Hanta viruses, do not spread quickly in human populations.

H.I.V. is an exceptional virus. We know from recent work that it did not evolve as a human pathogen but came into our society from apes. Like other viruses from animals, it cannot be contained by our immune system: Most people infected by H.I.V. who are not treated with powerful drugs ultimately die from the symptoms of AIDS. But unlike Ebola or the Hanta viruses, H.I.V. has evolved into a pathogen that humans can transmit to each other so effectively that it has produced an epidemic. That might not have happened earlier in this century, but changes over the past few decades in our sexual attitudes and practices, and in our patterns of drug use, have made it possible for H.I.V. to be transmitted sexually and by injection needles. Although the transmission of H.I.V. could be prevented if people modified their behavior, efforts to change or control the hazardous behaviors have never been more than partially effective. H.I.V. is now a virus endemic to human populations.

Why can't our immune system control H.I.V.? I doubt that we have all the answers, but we do know some key facts. To understand the situation, we need to realize that the immune system controls viruses in two distinct ways -- by producing antibodies and by programming cells called cytotoxic T lymphocytes.

Let's consider antibodies first. Antibodies were discovered in the early part of this century and are now well understood. They are proteins that can bind specifically to viruses and interfere with the viruses' ability to infect the body's cells. They neutralize a virus's ability to reproduce.

When people are infected by H.I.V., they produce lots of antibodies. However, this virus has found a way to keep the antibodies from doing their job: It does that partly by coating its proteins with sugar, which keeps antibodies from binding to them. That leaves only a little region of H.I.V. open to attack by antibodies, making it a difficult target to neutralize. In addition, the virus is able to change its structure so rapidly that the immune system cannot keep up with it. Antibodies are the first line of defense against most viruses, and H.I.V. has breached that line.

The immune system's other line of defense is cytotoxic T lymphocytes. Scientists discovered those cells only in the 1960s, and their action is so subtle that we still have many unanswered questions about them. However, we know that C.T.L.'s can completely control the growth of certain viruses in animals. We also know that in monkeys, C.T.L.'s can partly control simian immunodeficiency virus -- a virus analogous to the H.I.V. of humans. As shown recently by scientists in the laboratories of Norman Letvin at Harvard and David Ho at the Aaron Diamond AIDS Research Center in New York City, if most C.T.L.'s in an infected monkey are killed, the concentration of S.I.V. increases 10 to 1,000 times. We believe that C.T.L.'s limit H.I.V. in humans just as they do S.I.V. in monkeys. However, even though they are effective in humans, C.T.L.'s by themselves clearly cannot totally control H.I.V. in most people.

The task of making an AIDS vaccine is evident: Such a vaccine must stimulate the immune system to produce both antibodies and C.T.L.'s, preferably ones that are more effective than those created naturally when someone is infected with H.I.V. That is a tall order.

To put it in perspective, look at what other viral vaccines do. They start with an infection that is usually controlled by the immune system. The vaccine is necessary because, in some people, the virus maims or kills before the immune system can gain the upper hand. Thus, the vaccine's job is to stimulate an ordinary immune response but to make it appear sooner after infection. The vaccine stimulates the immune system in the same way that an ordinary infection does, but it uses as the stimulant either non-infectious material or an attenuated version of the virus in question -- that is, a version of the original virus that scientists have modified so that is unable to cause disease. The body reacts by producing antibodies and C.T.L.'s.

A few cells that make antibodies and a few C.T.L.'s are kept in a long-term storage reservoir in the body. We call them memory cells because they "remember" the stimulant. If the person is later infected by the virus against which he or she has been vaccinated, the memory cells are rapidly stimulated, and the immune system gets the upper hand in time to protect the infected person. There is still a transient infection, but it is rarely even perceptible -- the vaccine has turned an occasionally lethal infection into one that is benign.

But how could a vaccine control H.I.V.? With this virus, the issue is not one of speed of response. Infected people produce antibodies and C.T.L.'s -- although not particularly quickly -- and continue to produce them for years, but nonetheless the virus continues to spread until it finally kills. Furthermore, although scientists have tried to use an attenuated version of S.I.V. to produce a vaccine against that virus in monkeys, the vaccines that have been studied most intensively are not fully attenuated, and they eventually cause a disease that resembles AIDS. Efforts to produce a more attenuated virus are under way, but it may be that such a version of S.I.V. or H.I.V. would not in fact protect against disease.

Fortunately, other perspectives offer more hope. One involves examining the events that follow H.I.V. infection in humans. At first, the virus reproduces rapidly, reaching a very high concentration in the blood. But after a few weeks, the concentration falls, usually to a hundredth or even less than a thousandth of its earlier level, and remains at a plateau. The level of that plateau varies as much as 100,000 times from person to person. In an untreated person, the height of the plateau determines how quickly the patient develops AIDS.

Thus, if a vaccine were to lower the plateau, even if it didn't prevent infection, it might greatly delay the onset of AIDS. If it kept AIDS at bay long enough, it might in effect completely protect against the disease. It would certainly lower the rate of transmission. Vaccines with such properties have proved effective against S.I.V. in monkeys.

A vaccine of that sort probably works entirely through C.T.L.'s, which are thought to be the major agents in determining the level of the plateau. In fact, vaccines designed to cause the production of C.T.L.'s are well along in testing, and laboratories around the world are studying different modes of eliciting C.T.L.'s.

A second promising approach is a new concept of how to induce the production of antibodies that would neutralize the virus. Previous work has focused on developing a vaccine against the mature virus, but that has not resulted in antibodies that neutralize the virus efficiently. Jack Nunberg and his colleagues at the University of Montana have shown that much better results can be obtained by mimicking the early stage of the virus-cell interaction. Although the scientists have studied only mice so far, they have induced antibodies that recognize the virus more effectively than do antibodies elicited by the mature virus. Work along those lines is very new, but it has given increased optimism to researchers in the field.

Other intriguing ideas are percolating, too. For instance, Bruce Walker, at Massachusetts General Hospital, has emphasized that another type of cell, the T helper cell, occurs at particularly high levels in people whose H.I.V. infection is at a very low plateau. Such people often show little or no progression toward the development of AIDS. Perhaps scientists should try to develop a vaccine that would elicit T helper cells.

Will we have an AIDS vaccine, and when? Only a fool would attempt to answer those questions. However, everyone involved is working hard to try to make the answers "yes" and "soon." The U.S. government is putting almost $200-million into the effort for fiscal 1999. A new National Institutes of Health laboratory devoted to work on an AIDS vaccine is now under construction in Bethesda, Md.; it will be directed by Gary Nabel from the University of Michigan.

Two years ago, President Clinton gave us a decade to develop an AIDS vaccine. Will we make that deadline? With the formidable obstacles in our way, our inability to answer the question is understandable, even if it is frustrating. However, it is hard to believe that, with a veritable army of investigators at work, we will not succeed.

David Baltimore is president of the California Institute of Technology.


http://chronicle.com
Section: Opinion & Arts
Page: A64

Copyright © 1999 by The Chronicle of Higher Education


Sentence Outline

  1. But do most people understand the scientific challenges involved in producing such a vaccine?
  2. Unquestionably, no more important goal exists in medical research today than the development of an AIDS vaccine.

Why AIDS is different from other viruses.

  1. Can we make an AIDS vaccine? or History is a poor guide when it comes to this killer.
  2. Our immune system can effectively interfere with the multiplication of any virus that spreads solely among humans
  3. H.I.V. is an exceptional virus. or H.I.V. is now a virus endemic to human populations.

How immune system works.

  1. Why can't our immune system control H.I.V.? (Introduces two distinct responses: antibodies and cytotoxic T lymphocytes.)
  2. Let's consider antibodies first.
  3. When people are infected by H.I.V., they produce lots of antibodies.
  4. The immune system's other line of defense is cytotoxic T lymphocytes.
  5. Really a summary.The task of making an AIDS vaccine is evident: Such a vaccine must stimulate the immune system to produce both antibodies and C.T.L.'s, preferably ones that are more effective than those created naturally when someone is infected with H.I.V.
  6. A few cells that make antibodies and a few C.T.L.'s are kept in a long-term storage reservoir in the body.

Strategies for designing a virus.

  1. But how could a vaccine control H.I.V.? With this virus, the issue is not one of speed of response.
  2. Fortunately, other perspectives offer more hope. One involves examining the events that follow H.I.V. infection in humans. (Then introduces: rapid reproduction of virus, subsequent slow 100-fold decay to a plateau level.)
  3. Thus, if a vaccine were to lower the plateau, even if it didn't prevent infection, it might greatly delay the onset of AIDS.
  4. A vaccine of that sort probably works entirely through C.T.L.'s, which are thought to be the major agents in determining the level of the plateau.
  5. A second promising approach is a new concept of how to induce the production of antibodies that would neutralize the virus.
  6. Other intriguing ideas are percolating, too.

Conclusion.

  1. Will we have an AIDS vaccine, and when? ... However, everyone involved is working hard to try to make the answers "yes" and "soon."
  2. However, it is hard to believe that, with a veritable army of investigators at work, we will not succeed.