AFRO-NETS> New York Times: The AIDS Questions That Linger

[Cecilia Snyder <csnyder@ccmc.org>]

New York Times: The AIDS Questions That Linger
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January 30, 2001 

The AIDS Questions That Linger
By Lawrence K. Altman, M.D.

In the 20 years since the first cases of AIDS were detected, scien-
tists say they have learned more about this viral disease than any 
other, and few have disputed the claim. Scientists quickly discovered 
H.I.V., the AIDS virus; developed a test to detect it; learned the 
three main routes by which H.I.V. was transmitted (sexual inter-
course, contaminated blood and other body fluids, and pregnant 
mother-to-child); and found drugs that slowed progress of the infec-
tion, allowing many people to have relatively good health. 

Despite the gains, H.I.V. ranks among history's worst epidemics; 21 
million have died and 36 million more are now infected. H.I.V.'s toll 
has vastly exceeded the most pessimistic report issued earlier in the 
epidemic, and the misjudgement largely reflects gaps in knowledge 
about H.I.V. and AIDS. As a number of early beliefs and published 
scientific reports about AIDS have been overturned and work pro-
gresses slowly, discoveries like the identification of H.I.V. - as 
difficult as they were - are now viewed as the easy part of AIDS re-
search. 

When scientists meet next week in Chicago to present hundreds of pa-
pers about H.I.V. and other retroviruses, the gains reported are 
likely to be incremental in narrow aspects of research, not major 
breakthroughs. "People say that the more we learn about H.I.V., the 
more we realize we don't know a whole lot," Sandra Thurman said in an 
interview shortly before leaving the White House as the top AIDS of-
ficial in the Clinton administration. 

Dr. Anthony S. Fauci, the director of the National Institute of Al-
lergy and Infectious Diseases, said, "It is the rare person who gets 
up and strips himself of his personal agenda and articulates what we 
really do not know because by saying that they would diminish the im-
pact of their own work, which is their agenda." Yet Dr. Peter Piot, 
who directs the United Nations AIDS program, and Dr. Stefano Vella of 
Rome, the president of the International AIDS Society, and other ex-
perts say reviewing unanswered questions could prove useful as a 
measure of progress for AIDS and other diseases. Such a list could 
fill a newspaper, and even then would create debate. 

Because research has become so superspecialized, individual scien-
tists often focus on questions in their own area of work, making it 
difficult to achieve consensus on a broad area. Still, important 
broader scientific questions remain. Many have existed since the 
start of the epidemic; others developed later. In scores of inter-
views in recent months, a number of outstanding questions emerged. 
Among them are these:
Why does AIDS predispose infected persons to certain types of cancer 
and infections and not others? A longstanding belief is that cancer 
cells constantly develop and are held in check by a healthy immune 
system. But AIDS has challenged that belief. People with AIDS are 
much more prone to certain cancers like non-Hodgkins lymphomas and 
Kaposi's sarcoma, but not to breast, colon and lung, the most common 
cancers in this country. This pattern suggests that an impaired im-
mune system, at least the type that occurs in AIDS, does not allow 
common cancers to develop. The incidence of lymphomas has declined 
since the introduction of more potent anti-H.I.V. drugs in 1996, but, 
for unknown reasons, it has declined less than Kaposi's sarcoma and 
many other serious complications of AIDS, said Dr. Harold W. Jaffe, 
an AIDS expert at the Centers for Disease and Prevention in Atlanta. 
No one knows how significant a problem lymphomas will become as more 
people live longer with H.I.V. 

Equally puzzling is why AIDS patients are also more prone to infec-
tions like pneumonia caused by the pneumcystis carinii fungus, sys-
temic infections caused by M. avian bacteria and meningitis caused by 
the cryptococcus fungus. Studies of the immune system have not an-
swered the question, and "we do not know very much more about why 
that is than we did 20 years ago when the first work was done," said 
Dr. Henry Masur, an official at the National Institutes of Health. 

What route does H.I.V. take after it enters the body to destroy the 
immune system? When H.I.V. is transmitted sexually, perhaps through 
semen into the vagina, the virus must cross a tissue barrier to enter 
the body. How that happens "is still unclear," said Prof. Michel Ka-
zatchkine, the director of the French national agency for AIDS re-
search in Paris. The virus might invade directly or be carried by a 
series of different kinds of cells. Eventually H.I.V. travels through 
lymph vessels to lymph nodes and the rest of the lymph system. But 
what is not known is how the virus proceeds to destroy the body's CD4 
cells that are needed to combat invading infectious agents. Mapping 
the full route would give researchers new targets to block the virus 
and possibly prevent infection. "We need a breakthrough" in finding 
improved techniques to tag lymph cells to compare how infected and 
noninfected cells travel through the body as a way to better under-
stand how H.I.V. destroys CD4 cells, said Dr. David A. Cooper, an 
AIDS expert in Sydney, Australia. Information about H.I.V.'s entry 
into the body is key to developing a topical microbicide for use 
among women to block the virus from entering the body after sexual 
exposure and thus preventing infection. 

How does H.I.V. subvert the immune system? Although H.I.V. kills the 
immune cells sent to kill the virus, there is widespread variation in 
the rate at which H.I.V.-infected people become ill with AIDS. So 
scientists ask: Can the elements of the immune system responsible for 
that variability be identified? If so, can they be used to stop pro-
gression to AIDS in infected people and possibly prevent infection in 
the first place? The answers could soon be translated into huge bene-
fits for the world, said Dr. William Schaffner, the head of preven-
tive medicine at Vanderbilt University's medical school. The informa-
tion could be the key to developing an effective vaccine, which is 
essential to stopping transmission. 

Anti-H.I.V. drugs suppress replication of the virus, which should 
give the functioning parts of the immune system a chance to eliminate 
remaining virus. That does not happen. "So something is bizarre about 
that that we don't understand," Dr. Fauci said. Although the immune 
system generally controls viruses after the first days of infection, 
some viruses continue to lurk in the body and later escape control. A 
notable example is the chicken pox virus that remains silent for 
years but then can cause shingles. Why that happens is another unan-
swered question. 

What is the precise function of H.I.V.'s genes? H.I.V.'s nine genes 
have multiple functions, but they are only partly known. A complete 
blueprint could provide new targets for developing drugs and vac-
cines. When the genes were identified shortly after the discovery of 
H.I.V. in the mid-1980's, each was named for what its function was 
thought to be. One gene was called nef (for negative factor) because 
it was thought to inhibit H.I.V. But now it turns out to have an op-
posite effect. Nef accelerates H.I.V.'s ability to infect, though the 
gene is not absolutely required for H.I.V.'s virulence. Likening 
nef's function to stepping on a car's accelerator, Dr. Warner C. 
Greene of the Gladstone Institute of Virology and Immunology at the 
University of California at San Francisco, said, "AIDS emerges more 
rapidly when nef is present than when it is absent." Researchers once 
hoped to develop an AIDS vaccine derived from strains of H.I.V. from 
which nef was deleted naturally or by design. Researchers focused on 
a small group of Australians who were inadvertently infected with a 
nef-deleted strain of H.I.V. through transfusions from one blood do-
nor. The donor and recipients were not treated and did not become ill 
for up to 17 years. The dream of turning the naturally mutant strain 
into a safe, effective vaccine was shattered when the donor developed 
AIDS in 1999. 

In the United States, an experimental vaccine made by deleting the 
nef gene from a simian AIDS virus provided strong evidence of protec-
tion against an AIDS-like virus in early tests in monkeys. However, 
longer-term follow-up showed that the vaccine caused the disease it 
was designed to prevent. 

What is the most effective anti- H.I.V. therapy? Doctors debate the 
best time to start anti-H.I.V. drugs or change them when resistance 
develops. The decisions vary according to each physician's experience 
and reflect recommendations from panels of experts whose advice is 
based partly on information from clinical trials and largely on con-
sensus and opinion. In theory, early treatment should offer the best 
chance of preserving immune function. But new recommendations to be 
issued at the AIDS meeting will back a shift from the policy of "hit 
early, hit hard" that was recommended in 1996. At that time drugs 
that block a key enzyme, protease, in the virus's life cycle, were 
added to combinations of older drugs. The drugs suppressed the amount 
of H.I.V. in the blood beyond levels that tests could detect. A few 
excited virologists raised hopes of a cure. But the new drugs do not 
completely eliminate H.I.V. from the body, so the medicines, which 
can have dangerous side effects, will have to be taken for a lifetime 
and perhaps changed to combat resistance. 

The new policy is expected to recommend that treatment be deferred 
until there are signs the immune system is weakening. The treatments 
are now so complicated that it is difficult, expensive and time-
consuming to answer basic and practical questions. What combinations 
of drugs should be started first and when? Why do side effects like 
unusual accumulations of fat in the abdomen and neck develop? Is it 
possible to predict who will get them or how best to treat them? The 
change in recommendation reflects the fact that many patients and 
doctors already choose to postpone treatment because of fears that 
they will have no other drugs to use when resistance and other prob-
lems develop later on. In any case, many suspect that antiviral drugs 
alone will not achieve long-term control of H.I.V., and will require 
the addition of immune system-based therapies that are now being 
tested or developed. One avenue being explored is treating for a pe-
riod of time and then stopping in hopes of stimulating the immune 
system to combat H.I.V. An unanswered question is: will it work any 
better than standard therapy? 

Drug companies, foundations and international agencies are trying to 
deliver anti-H.I.V. drugs to AIDS ravaged third world countries in 
Africa and elsewhere. But the potent anti-H.I.V. drugs can produce 
anemia, bleeding, kidney stones and other unwanted side effects, and 
close monitoring is needed. Another critical unanswered question is: 
what is the best way to deliver anti-H.I.V. therapy in the third 
world where medical facilities are scarce? Is a vaccine possible? 
There is little question that an effective vaccine is crucial to con-
trolling the epidemic. But many unanswered questions exist about 
whether and when one can be developed. 

When H.I.V.-1 was isolated in 1984, Margaret Heckler, the secretary 
of health and human services, promised an AIDS vaccine within a few 
years. Seventeen years later prospects for an AIDS vaccine still ap-
pear quite remote, said Dr. Neal Nathanson, the former head of the 
National Institutes of Health's Office of AIDS Research. More than 30 
experimental H.I.V. vaccines have been given to people in the earli-
est phases of testing. Yet only one has reached the stage of full 
testing, and there is considerable dispute over the degree of protec-
tion it will provide. A vaccine may turn out to be partly effective 
or fully effective. A partly effective vaccine may allow a recipient 
who later was exposed to H.I.V. from developing AIDS for many years 
even if the recipient's body could not completely eliminate the vi-
rus. But because H.I.V. eventually causes AIDS in virtually all un-
treated infected individuals, a vaccine recipient might develop AIDS 
years later. How many people would take such a risk from a partly ef-
fective vaccine? Most licensed vaccines protect about 90 percent of 
recipients. Consider an AIDS vaccine that fully protected a much 
smaller percentage. What is the minimum percentage of protected re-
cipients that health officials would accept to license it? 

H.I.V. strains that are transmitted in various areas of the world 
differ genetically and are divided into subtypes. It is not known 
whether a vaccine derived from one type of H.I.V. will confer protec-
tion against other types. "The vaccine industry is trying to develop 
vaccines without having a clue if the subtypes are important to pro-
tection," Dr. Jose Esparza of the United Nations AIDS program said. 
Scientists also do not yet have some basic information about vaccines 
against H.I.V. For instance, they do not yet know which antibodies 
produced in response to a vaccine indicate the greatest likelihood of 
protection, a crucial step in developing any vaccine. 

Dr. Mark Wainberg, an AIDS researcher at McGill University in Mont-
real who was president of the group that sponsored the international 
AIDS conference in Durban, South Africa, last July, was asked there 
when an AIDS vaccine would be available. When Dr. Wainberg answered, 
"Not for at least 10 years," the questioner replied that it was the 
same answer he had given five years earlier. "He was right," Dr. 
Wainberg recently recalled. "Unfortunately, we still don't have the 
knowledge to create an effective vaccine, and I honestly don't know 
if we will ever have one because the problems are so great." 

In the absence of a vaccine, how can H.I.V. be stopped? Prevention 
programs that emphasize use of condoms, abstinence, H.I.V. testing 
and counseling have helped reduce infection rates in countries like 
Senegal, Thailand and Uganda and in a number of communities else-
where. Standard prevention messages are effective for many people but 
will not work for everyone because knowledge is still primitive about 
how young adults perceive risk and how attitudes can be changed. 
Without more incisive, focused behavioral research, prevention mes-
sages alone will not stop the global epidemic. 

Studies in Africa have shown a strong correlation between the amount 
of H.I.V. in the blood and risk of transmission. Presumably the re-
duced risk in such people reflects a decline in amount of H.I.V. in 
their genital secretions, lowering the ability to transmit the virus. 
However, only rare studies have tried to prove the point. Mathemati-
cal models suggest that wide-scale treatment in heavily infected 
countries can reduce transmission of H.I.V. But proving the models 
correct in everyday life would require trials in which large numbers 
of infected members in a community, or a community itself, receive 
anti-H.I.V. therapy while other members, or another community, do 
not, raising ethical questions and the possibility that some will 
falsely believe they are protected. 

Why do most babies born to infected mothers escape infection? Up to 
25 percent of babies born to H.I.V. infected mothers become infected. 
Why do the other 75 percent escape? Do these infants manage to mount 
a successful immune response to avoid infection? Relatively little 
research has been done to answer these and other questions, said Dr. 
Esparza, the U.N. official. 

Why do H.I.V. rates differ so greatly among regions in Africa and 
elsewhere? H.I.V. infection rates vary tremendously in Africa, which 
is the most heavily infected continent, and discerning the reasons 
could go a long way in stopping further transmission of the virus. 
Botswana has the highest H.I.V. infection rate in the world, 35.8 
percent among an adult population of 775,000. Neighboring South Af-
rica has the largest number of infected people, 4.1 million, and an 
infection rate of 20 percent among 20.6 million adults. In West Af-
rica, country rates range from 1 percent to 11 percent. A number of 
theories have been advanced to explain the regional differences, Dr. 
Jaffe of the C.D.C. said. One theory involves differences in the pat-
terns of sexual activity, including number of sexual partners, age at 
first intercourse and frequency of sexual contact with prostitutes. A 
second theory relates to the frequency of other sexually transmitted 
diseases, particularly those that break the skin, thus easing entry 
of H.I.V. A third theory relates to other coexistent infections such 
as malaria or tuberculosis that can increase the amount of H.I.V. in 
the blood, increasing their ability to transmit the virus. A fourth 
theory relates to circumcision; uncircumcised males appear to be more 
susceptible to H.I.V. than circumcised men. A fifth theory relates to 
virological differences among the subtypes of H.I.V. circulating 
within Africa that would favor transmission of one over the other. 
Despite studies, there is no simple explanation for the regional dif-
ferences, said Dr. Piot, the U.N. AIDS official. 

How many people are infected in the United States and has the rate 
changed in recent years? The precise number of infected people is not 
known because while all states must report AIDS cases, only 36 report 
H.I.V. infections. Since it takes 10 years on average for H.I.V. to 
progress to AIDS in the absence of treatment, newly reported AIDS 
cases reflect viral transmission about a decade ago. The Centers for 
Disease Control and Prevention estimates that in the last decade the 
number of newly infected people in this country has remained stable 
at 40,000 a year. Gay men accounted for about 40 percent of all in-
fections in 1999.

Where did AIDS come from? We can only guess. Determining the answer 
would be important because discovering how AIDS came to be epidemic 
might prevent a similar catastrophe in the future.

********************************
from nytimes.com Copyright 2000 The New York Times Company. Reprinted 
by Permission. New York Times material may not be used in any manner 
except for personal reference without the written permission of The 
New York Times Company. 
********************************

Cecilia Snyder 
Senior Project Associate
Communications Consortium Media Center
1200 New York Ave NW Suite 300
Washington DC 20005-1754, USA
Tel: +1-202-326-8711
Fax: +1-202-682-2154
mailto:csnyder@ccmc.org
http://www.ccmc.org

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