^Hundreds of Strains of HIV Virus Baffle Scientists<

^By Laurie Garrett=

^ 1991, Newsday=

Dr. Gerald Myers calls it ``the sugar-coated monstrosity.''

He wishes there were more glycosylation biochemists around who could try to

decipher the significance of the patterns of glycosylation seen with various

strains of HIV. One set of patterns is seen in HIVs found in brains, another

set in the babies of infected mothers, and so on.

Myers and a small staff of fellow computer experts at Los Alamos, N.M., run

GenBank, a data bank of DNA blueprints, or sequences of genes, that are the

code that produce viral proteins. Myers spends much of his time analyzing

approximately a thousand different sequences of an HIV component called V3,

which is one of the only proteins that protrudes from the sugar coating.

Because infected people do make anti-V3 antibodies, it's a likely vaccine

target. But the virus constantly mutates its V3 to elude such an attack. Myers

hopes continued computer analysis will reveal some V3 vulnerability common

among the hundreds of known HIV strains.

He has about 50 whole-virus HIV sequences in GenBank's supercomputer and

hundreds of pieces from HIV strains found all over the world. Long ago

scientists hoped computer analysis would uncover some common gene _ something

every HIV strain has and needs, which would serve as a target at which to aim a

drug.

Speaking in a deliberate monotone, Myers says he has identified at least

five distinct subtypes of HIV, and there may well be seven or eight subtypes in

the world. Within each subtype category are hundreds of different strains.

Haseltine says even within each infected person there are dozens of different

strains which mutate constantly, so that on any given day the genetic strains

of HIV may vary.

``For six years we've been staring at the horror of it,'' says Myers. ``The

virus, of course, is extraordinary. We've never really dealt with anything

quite like this before in medicine.

``It's just a formidable problem. There's loads and loads of data, but it's

noisy data, and we don't know what it means.'' Myers crunches data sent to him

by gene sequencers such as Steve Wolinsky. ``Ask Steve about his maternal-fetal

glycosylation patterns.''

At Northwestern University in Evanston, Ill., Wolinsky has been studying the

sugar coatings of HIVs taken from four mothers and their bebies; pairs from

Haiti, the United States and Rwanda, Africa. He has found that the HIV

glycosylations in the mothers are not the same as those in their babies.

But the surprise, Wolinsky says, was that all four babies, from different

parts of the world, had the same sugar patterns. He doesn't know what to make

of it except to note, ``The virus is a lot smarter than we are.''

^Distributed by the Los Angeles Times-Washington Post News Service<

**********************************************************************

^(ndy) (ATTN: News, Science editors) (Includes optional trims)<

^Despite Feverish Pace, Solution to AIDS Looms Decades in Future<

^By Laurie Garrett=

^ 1991, Newsday=

It's pitch black outside, but the halls of the National Institutes of

Health's Building 31, Wing A, in Bethesda, Md., are crowded with scientists

discussing their latest laboratory results.

It's been a long day, says Dr. Anthony Fauci, but then every day in the life

of America's chief of AIDS research is long, filled with administrative details

and meetings to plot the next step in the war against the elusive human

immunodeficiency virus. He won't get home until 10 p.m., after he addresses a

banquet at a major science conference in Washington. And he has to be back the

next morning in time for a 6:30 strategy meeting with colleagues linked by

telephone around the world.

``It's the only time this particular group can get together. We're all so

busy. Six-thirty, can you imagine?'' says Fauci, as he plops down into a

leather armchair, his energy belying the lack of sleep and the daily stress he

carries.

Ever since Magic Johnson announced he was infected with HIV, the phones have

been steadily ringing as congressmen, constituents and journalists want to know

what will happen to the basketball superstar. Even Vice President Dan Quayle _

who at first said that sexual abstinence was the ``sure cure'' for AIDS _ that

morning said that it ``would be wonderful to have a cure for AIDS in the

marketplace before Magic Johnson gets AIDS.''

``People ask, `Why has it taken so long to take care of HIV when we've taken

care of all other infectious diseases so quickly?' '' Fauci says. ``They forget

it took decades and decades to get rid of polio and smallpox. HIV is moving

along very quickly, but we still are in the middle of an out-of-control

epidemic.''

As Fauci heads off to his speech, Dr. William Haseltine gets his second wind

and pushes another late night at the Dana-Farber Cancer Institute in Boston

where his team may have identified exactly how the virus is sexually

transmitted.

Meanwhile, Drs. Gerald Myers and Flossie Wong-Staal are winding up their

work days. Myers commands a vast computerized network of genetic information at

New Mexico's Los Alamos National Laboratory, building a map of how the virus

changes and evolves. And Wong-Staal's work on the basic biology of HIV, first

at the National Cancer Institute, in Bethesda, and now at the University of

California, San Diego, is aimed at finding a way to pierce the virus'

formidable genetic armor. As Haseltine parks at home, Dr. Francoise

Barre-Sinoussi is just starting her day at the Pasteur Institute in Paris where

she is analyzing a mysterious strain of the virus found in Zaire that seems to

be an especially fast killer. It was her adept touch that finally in 1983

teased the mysterious virus out from the cells of sick Parisian men.

Meanwhile, in Geneva, researchers from all over the world are in a telephone

conference call with Dr. David Heymann, who leads up the World Health

Organization's effort to coordinate global AIDS drug-and-vaccine research.

All of these, and thousands more throughout the world are part of the

largest medical hunt since the discovery of a vaccine for polio. Though it left

millions crippled, polio rarely claimed the lives of its victims. HIV disease

is almost always fatal. Up to 11 million people are already infected, the World

Health Organization says, and despite expenditures of billions of dollars on

treatment, prevention and research, the epidemic is expected to hit 40 million

in just nine more years.

None of these scientists, nor dozens of other leading AIDS experts

interviewed last week, are optimistic about finding a cure for the deadly

disease because the virus acts on the most basic human level and can change its

form faster than science can aim. An effective vaccine, some way to prevent the

virus' spread, is probably decades away.

``It's incurable,'' Wong-Staal says, without hesitation, of HIV, ``because

it is a retrovirus and it integrates into the chromosomes of the host. And once

it's there it cannot be removed.''

Because there is no way to destroy the virus once it worms its way into the

human cell, the search is on for what Fauci and others call a functional _ as

opposed to an actual _ cure for AIDS. The virus would survive but would be kept

at bay by a combination of drugs that is relatively non-toxic and can be taken

for years. Some drug would boost the beleagured immune systems and others would

control infections by microbes that take advantage of the patient's weakened

state.

``That, for me, is a reasonable goal to shoot for in the next decade,''

Fauci says.

In the first decade of the AIDS epidemic, scientists discovered that HIV

caused the disease by destroying cells in the body's immune system. As the

numbers of the cells _ called CD4 T-cells _ declines, the body's ability to

stave off opportunistic infections shrinks. People succumb to a wide range of

secondary disease such as tuberculosis, yeast infections and pneumonia.

There are few weapons in medicine's arsenal that are effective against any

viruses, as seasonal flu sufferers well know. HIV is orders of magnitude more

difficult to tackle than a garden-variety virus because it is one of only three

known human retroviruses.

The usual viruses are essentially tiny packages of genes, usually in the

form of DNA or deoxyribonuclueic acid. Human cells also contain DNA genes which

are the blueprint for growth. To make proteins _ the building blocks of cells _

DNA must be translated into smaller RNA blueprints.

Viruses containing DNA are usually large because their genes have to include

all sorts of directions regulating their own reproduction. Their bulky size

makes DNA viruses relatively easy targets for the body's immune system. But in

the mid-1960s Howard Temin and David Baltimore discovered some viruses pulled a

sneaky genetic trick to evade the defenses of animals and plants they infect.

These viruses, dubbed retroviruses, contain tiny pieces of RNA, rather than

bulky DNA. When retroviruses infect cells, they literally insert their genes

into the host DNA. Once inside, the viral genes can hide for years, or

commandeer the cell's genetic and protein-production systems to make tens of

thousands of more viruses. The immune system barely has a chance to see the

enemy before the body is overrun.

The human immunodeficiency virus, like all retroviruses, cannot be removed

from a person's DNA once it has infected the individual's cells. So, scientists

say, it is incurable.

``We've learned enough about the virus to know there will be no easy cure,

no magic bullet,'' Haseltine says. ``Ultimately, the effective treatment will

come from ... an entirely new class of drugs.''

So far, three drugs have been discovered _ two of them licensed by the Food

and Drug Administration _ that offer hope of giving some patients additional

months of life. All three _ AZT, ddI and ddC _ block the ability of the virus

to reproduce. Unfortunately, their blocking effects are both fairly toxic to

the body and fail after a while because the virus overcomes the drugs by

mutating. HIV becomes resistant to these drugs within a matter of days in some

patients, months in others.

``By now, scientists have tested almost all the drugs available and many

chemicals which have the potential to be drugs,'' Haseltine says.

In the past 10 years, various drugs have sparked waves of enthusiasm among

scientists and from patients, desperate to grasp any straw. But the history of

the epidemic is littered with dashed hopes and false starts.

Until recently there was excitement about a class of European HIV-blockers

called TIBOs, but clinical trials show the drugs are quite toxic, says Fauci.

More importantly, Haseltine notes, TIBO-resistant HIV strains appear within

three weeks, rendering the drugs useless.

``Things couldn't be worse right now,'' says AIDS patient and leading New

York activist Larry Kramer. ``Nothing is panning out; the current drugs aren't

working. We also know that everything in the pipeline is turning out to be a

dud. So we're in major, major trouble.''

The picture is not only gloomy for people, such as Kramer, who already have

AIDS, but also for those, such as Magic Johnson, who are in the early stages of

HIV infection. Haseltine doubts any of the therapeutic approaches considered

promising just a year ago will pan out.

Science has eliminated the easy options and can now focus on those which

require greater intellectual leaps, Haseltine says. We've ``also examined

extracts of hundreds of thousands of plants, including the ingredients of the

traditional medicines of China, India and South America. Despite this massive

effort of traditional drug discovery, we still don't have drugs that do

anything but slow the progression of the virus.''

Gazing from his office window at a crisp autumn Boston sunset, Haseltine

heads the world's only academic division of retroviral research, staffed by

nine senior scientists and 51 other researchers.

Nearly all are working on what they call ``the AIDS problem.''

Their weekdays begin at 7 a.m. and rarely end before 11 p.m.; most of the

staff also works Saturdays and Sundays. Even as his group works, Haseltine is

training the next generation of potential AIDS researchers. Harvard graduate

students munch tortilla chips and gulp Diet Cokes as they listen to Haseltine

describe his latest findings.

``These are dendritic cells,'' he tells them, pointing at the large billowy

white blobs on the projection screen. He goes on to explain that the cells are

found in mucosal areas, such as the linings of the rectum, male and female

genitals, stomach and mouth. It is these cells _ even more than the cells of

the immune system _ that are the real HIV targets. When HIV gets into dendritic

cells, it can multiply many times over but remain hidden from the immune

system. When the virus is ready to pounce, it can flood the body suddenly with

whole armies of viruses, secretly manufactured inside the dendritic cells.

Recent studies in California and Britain have caused a sensation in the AIDS

world because they show that monkeys vaccinated against HIV may be immune if

the virus tries to infect through the blood stream. But the monkeys can still

get SIV _ the simian equivalent of HIV _ if the virus attacks through their

rectums or genitals. Haseltine thinks that means the virus easily enters

dendritic cells, evading even a supposedly vaccinated immune system. If the

monkey studies hold up, implications for vaccine development, prevention of

transmission and treatment are enormous because they more accurately explain

how the virus may be passed.

^(Begin optional trim)<

Haseltine, like most virologists, relies on other scientists to do suchanimal work.

``I wish we could make a vaccine without using animals, but it simply is not

possible. It would be great if you could develop vaccines without animals, but

I know of no way,'' says Dr. Ronald Derosier, head of the New England Primate

Research Center, center's molecular biology program. In 1984, Derosier

discovered SIV. He and colleagues at perhaps a dozen leading primate centers

around the world use the SIV model as a way of learning what might slow the

seemingly inevitable march towards death.

``What's remarkable about the SIV model is how closely it correlates with

the HIV human model, point for point, down the line,'' Devosier says.

His labs have found that by deleting a gene, called ``nef,'' from the SIV,

all viral replication stops. Animals loaded with nef-deleted viruses stay

completely well. Derosier isn't sure what implications _ if any _ the finding

might have for human treatment.

He's also uncertain about the possibility of developing a vaccine for AIDS,

although he considers it the most urgent priority in the epidemic. Saying

researchers are still at ``square one'' in their vaccine effort, Derosier

wonders aloud how the immune system could ever tackle viruses, such as SIV and

HIV, which cloak themselves in layers of sugar and carbohydrates, a process

called glycosylation.

``It is interesting that these SIV and HIV envelopes are among the most

heavily glycosylated proteins known to man,'' Derosier says. ``We don't know

what that glycosylation is doing.''

On one end of his office sofa sits a neat pile of manuscripts Derosier must

review for possible publication in a scientific journal. As he discusses the

curious sugar-coating of HIV, Derosier taps a manuscript by Dr. Gerald Myers.

It's awfully curious, Derosier notes, that in both SIV and HIV the sugar

coating covers nearly the entire virus, leaving no protein targets easily

vulnerable to the immune system.

It's what Myers calls, ``the sugar-coated monstrosity.''

^(End optional trim)<

Scientists, such as those in Wong-Staal's modern facilities in La Jolla,

Calif., are trying to outsmart the virus by figuring out which genes are most

crucial to all HIVs and to find a way to shut them off. Tlere are several

possible targets, she says, and theoretically a long list of ways to get at

them. But the key word is theoretically.

Such approaches that target HIV genes are called gene therapy. Fauci says,

``Gene therapy is obviously exciting to everyone because of the potential,'' of

completely reversing viral infection, ``but there is a large leap between

theoretical possibility and the realmty of making genes inside cells in the

human body.''

Haseltine puts it more bluntly: ``Although we have gene dreams, or Star

Wars, there are fundamental problems we don't understand and can't

circumvent.'' Uppermost, he says, is the confounding ability of HIV to mutate

around virtually anything thrown its way. And nobody knows how to effectively

get such genetic weapons inside the cells of living human beings.

If there is any bright spot in the epidemic, it is the increasing

international cooperation. ``I'd say there's really an international effort

right now, well orchestrated,'' says WHO's Heymann. It can be felt at all tiers

of the epidemic; in the clinics, in the development of drugs to treat the

secondary infections of people with AIDS, in the hunt for anti-HIVs and in

vaccine research. Most dramatically, within two years scientists from private,

government and coporate centers throughout the world are hoping to conduct

field trials of HIV vaccines in four developing countries. While none of the

candidate vaccines are considered effective at this point, the hope is that

such trials will provide researchers with the crucial information needed to

lead to a second generation of useful vaccines, though that could take decades.

``Our Holy Grail is vaccines because an effective vaccine would truly save

the world,'' Haseltine says. ``Every day we don't vaccinate, we're signing the

death certificates of 5,000 more people.

``Nobody can say with certainty when, or ever, there will be an effective

vaccine,'' he continues. ``We don't yet have a fundamental knowledge base to

make that prediction.''

^(Optional add end)<

The questions now most debated are whether the global basic research effort

needs more money and whether it should be more strictly coordinated, along the

lines of World War II's Manhattan Project that resulted in the atom bomb.

``It's not like saying go out and make a bomb. To completely Manhattanize it

would take away from the creativity,'' Fauci says.

But AIDS activists, particularly those infected with the virus, feel that in

the absence of a game plan, time is being lost.

And it all comes down to funding, says Jeffrey Levi of the AIDS Action

Council in Washington.

``One reason we don't have a plan is we don't have the resources we need,''

he asserts. And on that point _ lack of funding _ scientists and activists seem

to be in wholehearted agreement.

``As an adviser to many government programs, I can say with authority that

the federal budget for fundamental research on AIDS is inadequate,'' Haseltine

says. ``There are many promising research initiatives which go unfunded and

under-explored as a result of the failure of the government to provide enough

money for research. The federal research budget for AIDS has been frozen for

two years, in real dollars. From that same budget, the Congress and the Public

Health Service have demanded it cover more and more research initiatives.''

^Distributed by the Los Angeles Times-Washington Post News Service<

******************************************************************

^bc-aids-post 2takes<

^(wap) (ATTN: National editors)<

^AIDS Threat to Heterosexuals More Serious Than Thought Earlier<

^By Malcolm Gladwell=

^ 1991, The Washington Post=

Basketball star Earvin ``Magic'' Johnson's statement last week that he was

infected with HIV by a woman has focused attention on the forgotten side of the

American AIDS epidemic: the threat posed by the virus to heterosexuals.

Only a small number of the close to 200,000 Americans diagnosed with AIDS

are thought to have acquired HIV in the same manner as Johnson. And for years

public health officials have called HIV transmission between a man and a woman

a rare event, likely to happen only once in every several hundred sexual

encounters where one partner is infected.

But those numbers mask a more complicated reality. Although on average the

chances of acquiring the virus heterosexually remain low, recent scientific

findings suggest that because so many different factors affect the odds of

transmission _ and the virus itself is so cunning _ the contribution of

heterosexual sex to the American epidemic is as much to be feared under certain

circumstances as sharing needles or engaging in anal intercourse.

Heterosexuals who have other infectious diseases, or who have sex at the

very beginning or end of their HIV disease, are more infectious than they would

be otherwise. Some strains of HIV are more infectious than others. Women are

more at risk than men; younger women more so than older women.

The combination of these factors, and others, has already made heterosexual

transmission the dominant cause of the epidemic's spread in Africa and Asia. In

the United States, where the rate of heterosexual transmission is rising, AIDS

experts call the recent statement by Johnson that he was infected by a woman

only the tip of the iceberg.

``There has been skepticism about whether heterosexual transmission of HIV

is a problem,'' said King Holmes of the University of Washington, one of the

country's leading experts in sexually transmitted diseases. ``This is really an

extraordinarily narrow perspective when one realizes that on a global basis, 75

percent of HIV is being transmitted sexually, much of it heterosexually. To

think that in the U.S. we would be any different is peculiar.''

``We have all been a little too optimistic about heterosexual

transmission,'' said Andrew Moss, an epidemiologist at University of San

Francisco. ``We have been lulled by the apparently low rates of male-to-female

transmission. It is time to think about it more.''

Of the 192,000 people in the United States currently diagnosed with AIDS,

10,989, or about 6 percent, are thought to have contracted the disease

heterosexually. Experts say there are two reasons the number is not higher.

First, the epidemic first struck gay men and has been slow to reach the

heterosexual community. This year, Holmes estimates, between 10 percent and 15

percent of all new infections with HIV will be the result of vaginal

intercourse, and among certain categories of inner-city youth the share of new

infections attributable to heterosexual transmission is even greater.

The second reason AIDS among heterosexuals has remained low is explained by

the relatively slow rate at which it has spread among straight men and women,

and the reason for that is biological. HIV is a virus that lives in the white

cells of the bloodstream. These are the cells of the immune system that it

gradually destroys. So any kind of blood-to-blood contact is the most efficient

way to transmit the virus.

That is why the recipients of HIV-infected blood transfusions almost always

get AIDS. It is also why the sharing of syringes among drug addicts, where

needles carry traces of one addict's blood to another, so frequently results in

the spread of HIV.

Anal sex is considered the next riskiest mode of transmission, largely

because the sexual act can tear the walls of the rectum, allowing one partner's

semen _ which can carry infected white blood cells _ to come directly into

contact with another's blood.

According to some researchers, however, there does not have to be direct

blood contact for the virus to be transmitted from one person to another. At

the University of California at Davis, for example, scientists were able to

infect monkeys with SIV _ the close cousin of HIV _ simply by placing drops

containing the virus on the mucosal tissues inside the females' vaginas and in

the male's urethra. In each case, the virus was placed on undamaged tissue. The

theory here, backed up by other research, is that the virus can invade certain

kinds of cells _ known as dendritic cells _ that reach to the surfaces of both

male and female genitalia.

Some authorities say mucosal infection can explain why conventional vaginal

intercourse, even if it causes no bleeding, can result in HIV infection. Still,

mucosal infection is considered fairly uncommon. One reason vaginal sex is so

much less likely than anal sex to result in transmission of HIV is that vaginal

tissues are stronger than those of the anus and less likely to be damaged in

intercourse.

Exactly how low the risk of transmission among heterosexuals is, however, is

a matter of some dispute. In their computer modeling of the epidemic, some

epidemiologists say the risk of one infected heterosexual passing the virus to

another in a single sexual encounter is between 1 in 100 and 1 in 1,000. But

others dismiss the data on which it is based as flimsy.