Chemokines and HIV
by Mark Bowers
See also A History of Chemokines,
this issue.
In the last 15 months, basic research in AIDS pathogenesis, the study
of how HIV causes disease, has led to the creation of a new field of biomedical
research: the study of chemokines. The word "chemokine" is derived
from chemoattractant, a soluble factor that attracts white blood cells
to places where they are needed (e.g., sites of inflammation or infection),
and lymphokine, a chemical messenger that conveys important information
between lymphocytes (T-cells and B-cells). Chemokines bridge the communications
gap between lymphocytes and other cells of the immune system. Chemokines
are known to induce inflammation and to direct the migration of white
blood cells. A deeper understanding of this new field may help identify
new strategies to treat HIV disease, and may hold the key to an effective
vaccine.
Chemokines are secreted by various types of immune system cells. The
targets of chemokines are receptors, specialized docking areas on the
surface of white cells such as monocytes, lymphocytes, basophils and eosinophils.
Receptors are tailored to accept only specific shapes, and a chemokine
must link with an appropriate receptor. When a chemokine successfully
docks at or binds to a receptor, a cascade of events begins. This process
is referred to as signaling, or signal transduction. An example of signal
transduction is the sense of smell. Olfactory receptors are part of a
complex system whereby chemical molecules are translated into perceived
smells in the brain. Signaling is a basic part of recognizing the external
world.
Some receptors act as points of entry to a cell, and are called transport
receptors. The large proteins that are needed for healthy cells to function
are brought inside the cells via transport receptors. Transport receptors
can also play an important role in infection. For many years, it was known
that HIV could enter human immune system cells by binding to a receptor
called "CD4." However, other animals whose cells also have CD4
receptors did not become infected with HIV. There had to be another necessary
binding step. Researchers have been looking for an HIV "co-receptor"
in humans ever since.
When HIV binds to the surface of a T-cell or macrophage, a process is
initiated whereby the virus is pulled inside the cell. Recent research
has identified 2 "missing-link" transport receptors that are
found on the cell surfaces of the immune system cells most commonly infected
by HIV. Monocytes and macrophages have a different transport receptor
than do CD4 T-cells. Both of the receptors and several of the chemokines
that stimulate them were identified, and the study of chemokines was born.
The new field of chemokine research has progressed remarkably quickly.
Most of the research has been done by scientists trained to see the connections
between previously highly separate and independent areas of inquiry in
science and medicine. Some senior researchers have lent their reputations
and research clout to the new field, including HIV co-discoverers Robert
Gallo, MD, of the University of Maryland, Jay Levy, MD, of the University
of California at San Francisco, and Anthony Fauci, MD, of the National
Institute of Allergy and Infectious Diseases (NIAID). It has recently
been discovered that the congenital absence of a specific co-receptor
effectively protects some individuals from HIV infection.
Cell Antiviral Factor
Since 1986, Jay Levy has maintained that CD8 cells (cells that have a
CD8 receptor on their surface) secrete a soluble factor -- which he called
cell antiviral factor (CAF) -- that inhibits HIV replication in infected
cells. (See BETA, June 1995, pages 18-24 and 31-32, and September 1994,
page 15.) CAF works independently of the usual CD8 strategy for controlling
virally infected cells, which is direct destruction (cytolysis). So far,
Levy has been unsuccessful in isolating the factor, but his work has inspired
many other researchers to look for it. Indirect evidence for the existence
of such a factor or factors was described in studies of long-term nonprogressors
(people who do not lose T-cells or develop opportunistic infections despite
many years of HIV infection), and researchers began a lengthy process
of eliminating potential candidates. What human factor or factors account
for the fact that, in some people, HIV disease progression is very slow
or even absent?
In December 1995, it was shown that 3 chemokines -- RANTES, MIP-1a and
MIP-1b -- were made by CD8 cells. All 3 chemokines were able to inhibit
HIV replication in test tube studies. RANTES (regulated-upon-activation,
normal T expressed and secreted), MIP-1a and MIP-1b (macrophage inflammatory
protein-1 alpha and beta) were isolated in Robert Gallo's Tumor Cell Biology
Laboratory at the National Cancer Institute. These chemokines were able
to inhibit growth of the HIV taken from infected individuals, but not
the laboratory strain of HIV that is commonly studied (HIVIIIB). Gallo
and his colleagues proclaimed that they had solved Levy's puzzle. Levy
disagreed, and continues to work to isolate the CD8 factor.
Levy's confidence that there is a CAF is shared by Fauci at NIAID and
by researchers at Chiron Corporation in Emeryville, CA. They have found
that CD8 cells can inhibit HIV replication by some mechanism that does
not involve cytolysis (cell killing) or the 3 chemokines found in Gallo's
laboratory. There may well be receptors for CAF that also await discovery.
Alpha and Beta Chemokines
Alpha and beta chemokines are soluble factors that are secreted by immune
system cells. They have properties of both chemoattractants and lymphokines.
They are structurally similar, containing a single amino acid between
2 cysteine residues, a structure that is abbreviated by the shorthand
notation C-X-C. They primarily activate neutrophils. Beta chemokines are
similar to alpha chemokines, except that there is no intervening amino
acid between the cysteine residues, so the shorthand notation is C-C.
Their primary targets are monocytes, macrophages, lymphocytes, basophils
and eosinophils.
Alpha and beta chemokines have receptors on different target cells. In
harmony with the shorthand notation for alpha chemokines, their receptors
are designated CXCR-1, CXCR-2, CXCR-3 and CXCR-4. Beta chemokine receptors
are designated CCR-1, CCR-2A, CCR-2B, CCR-3, CCR-4 and CCR-5. RANTES,
MIP-1a and MIP-1b, the 3 beta chemokines discovered in the Gallo laboratory,
can dock at CCR-1, CCR-3, CCR-4 or CCR-5 receptors. The fact that a chemokine
can bind to more than one receptor does not mean that the receptors are
redundant, since the biological events that follow docking at CCR-1 can
be quite different from what happens after docking at CCR-5.
M-tropic and T-tropic HIV
Tropism refers to which cells an organism such as HIV prefers to infect.
The type of HIV that infects monocytes and macrophages is called M-tropic
virus. Macrophages and monocytes are specialized immune cells designed
to engulf bacteria, viruses and foreign particles, and to process them
for presentation to T-cells. Macrophages also act as the body's sanitation
engineers, clearing away foreign particles and organisms that have been
bound to antibodies. Macrophages represent a major reservoir for HIV in
humans. T-cells, the strategic planners of the immune system, secrete
various cytokines to communicate with macrophages and monocytes, direct
their activities, and tell them to replicate, grow or cease activity.
Macrophages and monocytes are the cells that are known to be infected
with HIV immediately after seroconversion (the first production of antibodies
against HIV following initial infection) and during the long preclinical
phase of HIV disease. M-tropic HIV replicates in peripheral blood lymphocytes,
but does not form syncytia (clumps of cells whose membranes have fused
together). Non-syncytia-inducing (NSI) strains of the virus are considered
to be less virulent than syncytia-inducing (SI) virus. SI virus is associated
with rapid disease progression and an unfavorable prognosis.
T-cells are divided into CD4 cells and CD8 cells. CD4 cells are the cells
that are continuously depleted during HIV disease. Strains of HIV that
infect CD4 cells are referred to as T-tropic. T-tropic HIV can also be
syncytia-inducing. Robin Weiss, PhD, of the Institute of Cancer Research
in London, speculates that the shift from NSI virus to SI virus reflects
a change in tropism from HIV that primarily seeks macrophages to HIV that
primarily seeks T-cells. The co-receptor for T-tropic virus is the alpha
chemokine receptor alternately called LESTR (leukocyte-expressed seven-transmembrane-domain
receptor), fusin or CXCR-4.
Tatjana Dragic and colleagues at the Aaron Diamond AIDS Research Center
in New York showed that HIV gains entry into CD4 cells by using the CCR-5
receptor to fuse the viral envelope to the host cell wall. CCR-1, CCR-2A,
CCR-3 and CCR-4 did not permit such fusion. The beta chemokines RANTES,
MIP-1a and MIP-1b can block this fusion.
Joseph Sodroski, of the Dana-Farber Cancer Institute in Boston, and colleagues
showed that M-tropic HIV could use either the CCR-5 or the CCR-3 receptor
to enter cells, and that a specific stretch of gp 120, a component of
the HIV envelope, interacts with these receptors. The stretch of gp120
that binds to the co-receptor becomes exposed only after gp120 binds to
CD4. The V3 (third variable) loop of the gp120 molecule then unfurls to
reveal the stretch that attaches to the CCR-5 receptor. T-tropic HIV employs
a similar strategy, binding first to CD4 and unfurling a slightly different
stretch of gp120 that then binds to the CXCR-4 receptor. With these discoveries,
the hope was raised that drugs that target these specific binding processes
could be quickly designed and tested.
A recent set of experiments done at the Gladstone Institute of Virology
in San Francisco established that the part of the CCR-5 receptor that
protrudes from the host cell contains several stretches of amino acids
that assist the entry of HIV into the cell. The receptor molecule snakes
in and out of the cell wall, leaving some parts exposed and others buried
inside the cell. Three loops and a tail extend from the cell surface,
providing several mooring clamps for HIV. Robert Atchison and colleagues
learned 2 important lessons from their experiments: (1) the structure
of CCR-5 can be altered so that normal function is not interrupted (the
cell still responds to the appropriate chemokines) but HIV cannot enter,
and (2) it may be possible to design a drug or other agent that blocks
the HIV co-receptor without triggering an unwanted biological signal,
as might happen with a naturally occurring chemokine.
At first the T-tropic receptor CXCR-4 was thought to be an orphan receptor
without any known ligand (molecule that binds to the receptor to initiate
a biologic process). In August 1996, it was reported that the only alpha
chemokine known to use the CXCR-4 receptor is SDF-1 (stromal cell-derived
factor). Estelle Oberlin, MD, and colleagues at the Pasteur Institute
in Paris, France, reported that SDF-1 prevents infection by T-cell-line-adapted
HIV-1, and suggested that a simultaneous blockade of both M-tropic and
T-tropic receptors using RANTES, MIP-1a, MIP-1b and SDF-1 could help to
decrease viral load and prevent the emergence of SI strains of virus.
The strategy is to bind all the potential co-receptors for HIV so that
HIV cannot infect any new host cells, and then wait for the immune system
to kill and dispose of the existing population of HIV-infected cells.
M-tropic and T-tropic strains of HIV coexist within the body. There is
no time when all of the HIV in a given individual is either M-tropic or
T-tropic, but apparently M-tropic virus must gain a foothold first before
infection with T-tropic HIV can be initiated. Why this is so is the subject
of considerable speculation. Some researchers believe that M-tropic virus
is particularly successful at infecting mucosal surfaces, which would
help explain why people who lack receptors for M-tropic virus do not become
infected with HIV despite regular unprotected sex. However, an absence
of these receptors also protects individuals from contracting HIV through
sharing needles or transfusions of contaminated blood products.
Correlates of Protection?
Studies of long-term nonprogressors have frequently focused on discovering
what sets them apart from those whose HIV disease progresses inexorably
to AIDS. Until the discovery of the CCR-5 co-receptor for HIV-1, there
were few clues about natural protection from infection. Richard Koup and
William Paxton at the Rockefeller University Aaron Diamond AIDS Research
Center studied 25 men who remain uninfected with HIV despite repeated
unprotected sexual exposure. They found 2 main distinctive features in
these men: (1) their CD8 cells had greater anti-HIV activity than CD8
cells taken from control subjects who had not been exposed to HIV; and
(2) their CD4 cells were relatively resistant to infection with M-tropic
HIV. Koup and Nathaniel Landau (also at Aaron Diamond) found 2 people
who had been repeatedly exposed but remained free of HIV infection, and
discovered that the genes that they inherited from both parents contained
a mutation: they produced a mutant CCR-5.
A subsequent collaboration including Stephen O'Brien, Michael Dean and
Mary Carrington at the National Cancer Institute proved that some people
who have a double genetic mutation for CCR-5 are highly resistant to HIV
infection. Looking for the genetic mutation in 1,955 people, O'Brien and
his team found that people with 2 copies of the mutant gene (and therefore
no normal CCR-5 receptors) were all uninfected, while people who have
1 copy of the mutant gene might progress to AIDS more slowly than those
with 2 completely normal genes for CCR-5. Marc Parmentier of the Université
Libre de Bruxelles in Belgium found at least 1 copy of the mutation in
17% of 704 Caucasians. However, no African (from Zaire, Burkina Faso,
Cameroon, Senegal and Benin) or Japanese DNA samples contained the CCR-5
mutation. O'Brien found the mutation in 11% of Caucasians and 1.7% of
African-Americans.
Although the genetic mutation that affects the production of CCR-5 has
been found only in Caucasians and in African-Americans, there is reason
to believe that there may be other mechanisms that account for the protection
seen in multiply-exposed, uninfected sex workers in Thailand and Zambia
(see BETA September 1996, page 53). As the field of chemokine research
matures, many as-yet-unknown receptors will likely be identified, and
more correlates of natural protection and nonprogression will emerge.
Basic research presented at the 4th Conference on Retroviruses and Opportunistic
Infections, held January 22-26, 1997, in Washington, DC, showed that several
kinds of immune system cells may express beta chemokines and block infection
with M-tropic HIV. Anthony Fauci, MD, and colleagues at the National Institute
of Allergy and Infectious Diseases (NIAID) demonstrated that natural killer
cells can secrete b chemokines that suppress HIV replication, and R. Kornbluth,
MD, and colleagues at the University of California and V.A. Medical Center
in San Diego, showed that macrophages in lymph nodes can produce large
quantities of b chemokines when stimulated by certain T-cells that carry
the CD40L molecule on their surfaces. These chemokines were collected
and subsequently protected T-cells from HIV infection in vitro.
Therapeutic Strategies
Previous attempts to block HIV from attaching to CD4 cells have failed.
Soluble CD4 was unable to act as a successful decoy for HIV, primarily
because the artificial decoys did not last long enough in the blood to
have a positive effect. Future attempts to block HIV binding, this time
to co-receptors, will probably face similar technical difficulties. Nonetheless,
some plausible targets for therapeutic interventions have been suggested,
and the direction of drug discovery is being established.
Fernando Arenzano-Seisdedos and colleagues at the Pasteur Institute,
with the help of Canadian and Swiss collaborators, have identified a new
chemical that looks like RANTES but does not activate cells when it binds
to the CXCR-4 receptor, nor does it attract white blood cells. It does,
however, block HIV infection. They concluded that therapeutic agents that
establish a blockade of the co-receptor are possible without creating
the severe side effects seen with the administration of other cytokines
such as interleukin 2 (IL-2).
Helena Schmidtmayerova and colleagues, of the Picower Institute for Medical
Research in New York, have demonstrated that the induction of beta chemokines
can inhibit or stimulate HIV replication, depending on what kind of cell
is stimulated and what kind of virus (M-tropic or T-tropic) is predominant.
Beta chemokines do not inhibit infection of monocytes or macrophages,
but they do inhibit infection of CD4 T-cells. These same chemokines increase
HIV replication in monocytes and macrophages and suppress replication
in T-cells. The researchers suggest that therapeutic strategies that allow
or encourage monocytes and macrophages to express chemokines may help
protect T-cells by encouraging HIV to remain M-tropic.
British Biotech has developed an analog of the chemokine MIP-1a as a
cancer therapy. A clinical study underway in London is recruiting 15 HIV
positive individuals with CD4 cell counts between 50 and 500 cells/mm3
to receive the compound BB10010. Other analogs are expected to be tested
soon.
A collaboration between LeukoSite, Inc., of Cambridge, MA, and the Dana
Farber and Children's Hospitals in Boston, along with Warner-Lambert's
Parke-Davis Pharmaceutical Research Division, intends to exploit the HIV
co-receptor function of CCR-5 in an effort to discover and develop new
antiviral drugs. The challenge will be to develop modified versions of
existing chemokines that can block the co-receptors but that will not
trigger the inflammation usually induced by chemokines.
Vaccine Design
Vaccine researchers are confident that the identification of the 2 co-receptors
for HIV will help them design animal models that will closely resemble
natural infection in humans. The lack of a suitable animal model has been
a stumbling block for HIV vaccine development. Only in chimpanzees can
HIV-1 replicate as it does in humans, and chimps are an endangered species.
Now that CCR-5 and CXCR-4 are identified, transgenic animals (ones in
which human immune systems have replaced their own immune systems) can
be genetically designed to exactly mirror the conditions for infection
in humans. Vaccine candidates could be quickly evaluated in these transgenic
animals before proceeding to difficult and costly human testing.
Now that some of the correlates of immunity to HIV infection are clearer,
several important question arise for the makers of vaccines. Can a vaccine
be made to induce chemokine expression? Which chemokines should be induced?
Should beta chemokines be induced in people who are already infected?
Given the clear evidence that a lack of CCR-5 receptors confers immunity
to HIV and appears to have no known negative consequences, researchers
are asking whether a vaccine could raise antibodies to selectively eliminate
CCR-5 receptors. Such a vaccine candidate would need to be limited to
CCR-5 receptors and would need to avoid inducing inflammation. Open questions
include what happens should binding to or destroying a CCR-5 receptor
result in the appearance on the cell surface of even more receptors (up-regulation).
Early in 1997, Immune Response Corporation presented data suggesting
that their vaccine candidate Remune induced chemokines in 15 study subjects.
Remune also induces increased production of gamma interferon, another
cytokine.
It seems likely that a combination approach will yield the greatest benefits.
Chemokines combined with combination antiviral drugs may prevent further
expression of HIV, and could potentially speed the process of weeding
out latently infected cells.
Research that must be done before proceeding with co-receptor-based vaccine
candidates includes learning exactly which part of HIV fits into each
co-receptor. If any part of that stretch of HIV remains visible to the
immune system instead of curled up and hidden inside gp120 until just
before binding to the co-receptor, then a vaccine that exactly mirrors
that stretch could be made.
Conclusions
Research is progressing rapidly in the area of chemokines and their receptors.
Dozens of practical applications are being drafted based on the breakthroughs
in knowledge about how HIV causes initial infection. Understandably, many
people will want to know if they have 1, 2 or no mutant genes for CCR-5,
the receptor whose absence confers apparent immunity to HIV. Currently,
assays to detect the genetic abnormality are available only to researchers.
There is concern that such individuals will incorrectly conclude that
they no longer need to practice safer sex, although there is no evidence
that they may safely do so.
Molecular biologists are interested in the workings of cells and infectious
organisms at the cellular level. The recent advances in chemokine research,
coupled with breakthroughs in understanding the mechanisms that bring
about programmed cell death (apoptosis) may ultimately explain the pathogenesis
of HIV disease in exquisite detail. However, it is not yet known how chemokines
achieve their HIV suppressive effects at the molecular level. Molecular
biologists would like to solve that mystery soon.
Three major diseases are known to exploit chemokine receptors. Cytomegalovirus
(CMV) makes a 7-transmembrane protein (CMV US28) that is very similar
to CCR-1 and is a functional chemokine receptor. The malarial parasite
Plasmodium vivax uses a chemokine receptor on red blood cells.
And HIV uses at least 2 chemokine receptors at different stages in the
disease process to continuously infect new cells. These 3 findings will
spur infectious disease specialists to better understand the pathogenesis
of each of these killer diseases and to look at other infectious diseases
that may also exploit chemokine receptors.
Recent research has revealed that the herpesvirus primarily responsible
for Kaposi's sarcoma, KSHV, makes its own chemokine receptor that may
be connected with the mechanism the virus uses to induce malignancies.
In February, Leandros Arvanitakis and colleagues at the Cornell University
Medical College, reported the discovery of GPCR, a receptor of the CXC
chemokine family that appears to have been pirated from a cellular gene.
It is active when stimulated with IL-8, a cytokine that stimulates the
growth of new blood vessels, possibly explaining the vascularization process
in KS. The receptor provides a new target for future KS therapies.
People with HIV/AIDS want immediate practical applications. They will
certainly want to avoid developing SI virus, and non-toxic strategies
to prevent the mutation in HIV that renders the virus aggressively lethal
to T-cells will be a welcome addition to currently available drug therapies.
Chemokine research shares the limelight with the protease inhibitor drugs
as the Science magazine "1996 Breakthrough of the Year." The
most significant developments in science in 1996 were in the field of
AIDS research, and the rewards of future research are only now being glimpsed.
Mark Bowers is Managing Editor in the Treatment Education and Advocacy
Department at the San Francisco AIDS Foundation.
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