From: Billi Goldberg <bigoldberg@igc.org>
Subject: Science Article dated 7/10/92
Note: non-commercial reproduction.
Archive-Number: 5740
Organization: UCLA, Computer Science Department
Date: Mon, 20 Jul 92 20:24:45 PDT

The following is summarized and excerpted from the July 10, 1992 issue 
of SCIENCE.  The article is very important in my opinion and should be 
read in its entirety.

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AIDS RESEARCH SHIFTS TO IMMUNITY

A decade into the AIDS pandemic, two widely held and fundamental 
assumptions about the progress of this scourge may be falling by the 
wayside--with potentially profound implications.

For much of the 11 years since the disease was first recognized, the 
vast preponderance of epidemiologists, researchers, and clinicians have 
believed that, even though most infected people do not get sick for 
years, ultimately all who are infected will fall ill.  Secondly, it has 
been the common wisdom, until quite recently, that repeated exposure to 
HIV through sex will virtually guarantee infection.  Now comes a slew of 
provocative studies being conducted at many different medical centers 
worldwide that are uncovering immunologic clues that may help explain 
why some people who have been infected since as far back as the later 
1970s have remained symptomlesss and why others, who repeatedly have met 
up with the virus, have remained uninfected.

As investigators begin to look hard at why some people stay healthy in 
the clutches of HIV, a basic shift in the focus of AIDS research is 
taking place: "For the past five, six years of this epidemic, people 
have been look at correlates of [disease] progression," say Bonnie 
Mathieson of the Division of AIDS, a branch of the National Institute of 
Allergy and Infectious Diseases (NIAID). "Now they're finally starting 
to look at correlates of protection."  And this new focus on immunity to 
HIV has already begun to make researchers question widely help 
assumptions about what an HIV vaccine needs to do.

...

But what if researchers get nowhere at actually blocking infection?  
That would make it more desirable to keep the virus, once established in 
a person's system, under control.  And there are recent indications the 
immune system may be able to keep the virus in check.

The search for humoral and cellular responses that might protect 
infected people has led David Ho, head of New York's Aaron Diamond AIDS 
Research Center, to home in on the very early period of infection
--attempting to find out how the immune system handles the virus's 
initial assault, which it often seems to do quite deftly.  During this 
"acute" phase of infection, the amount of HIV skyrockets to the levels 
seen in patients with full-blown AIDS.  Then, in most cases, the viral 
load plummets.  "That's without drugs," says Ho.  "It's spontaneous.  I 
happen to think that that is immune-response directed.  That's 
consistent with our understanding of immune control of other viral 
diseases."

Again, as in the case of those who may be showing natural immunity, the 
cellular arm of the immune system could be the key.  "Very, very 
preliminary evidence," say Ho, suggest that what is responsible for 
controlling HIV "is cell-mediated immunity."  Ho and his colleagues 
recently did a detailed analysis of one patient with acute HIV infection 
and found, much to their surprise, that the initial burst of virus was 
significantly knocked down before they could detect either antibodies 
that could latch onto the virus and neutralize it or a type of killing 
known as antibody-dependent, cell-mediated cytotoxicity (ADCC).  But the 
drop correlated with the appearance of CTLs, the killer lymphocytes 
that rid the body of infected cells and are a crucial part of the 
cell-mediated response.

...

All these studies--suggestive as they may be--are far from complete.  
Even so, they have already begun to offer some practical pointers for 
AIDS vaccine researchers.  The most immediate lesson could be a shift 
toward greater emphasis on cell-mediated immunity, which almost all of 
these studies indicate plays a large role in keeping the healthy that 
way.  To date, many AIDS vaccine developers have relegated cell-mediated 
immunity to a backseat, banking on their ability to crank up production 
of neutralizing antibodies.

...

That view makes sense, But, unfortunately, the evidence that 
neutralizing antibodies can protect a person from initial infection 
remains thin.  Most work on neutralizing antibodies has focused on 
trying to raise antibodies against a specific portion of the viral 
envelope--the so-called V3 loop.  Yet, save for a few influential 
chimpanzee experiments, precious little has been demonstrated in living 
organisms about the ability of V3 antibody to protect against infection.

As the cell-mediated data emerge from recent studies, however, some 
researchers are resetting their sights.  "I think there has been an 
overemphasis on neutralizing-antibody work," says Aaron Diamond's Ho, 
whose lab does much neutralizing-antibody work.  'The ideal vaccine 
would elicit good neutralizing antibodies and some cell-mediated 
immunity."

Others are even more emphatic.  Polio vaccine develop Jonas Salk, who 
co-founded San Diego's Immune Response Corporation to design an AIDS 
vaccine, has long contended that cell-mediated--not humoral--immunity is 
the key.  "The virus enters the host in a cell, whether the route is 
intravenous, seminal fluid, or vaginal secretions," says Salk.  "It's in 
a cell.  Therefore it's like a cancer cell, and the immune mechanism 
must be cell-mediated."
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