LIR investigators will make 11 poster and slide presentations during
the conference, which runs from Wednesday, January 22 through
Sunday, January 26.
LIR Chief and NIAID Director Anthony S. Fauci, M.D., comments,
"At the Washington meeting, our group will discuss new data from
laboratory studies and clinical trials that underscore the importance of
host factors to the pathogenesis of HIV disease. Our studies of the
soluble molecules which regulate HIV replication, the co-receptors on
immune system cells used by the virus for fusion and entry, and other
factors intrinsic to the HIV-infected individual suggest potential
strategies for the treatment and prevention of HIV infection."
Below are brief summaries of the LIR presentations. Information for
each is EMBARGOED UNTIL THE TIME OF PRESENTATION.
- Critical Elements of Fusin Gene Identified
Among the most significant research findings in AIDS research to date
is the discovery of co-receptors on immune system cells used by HIV
for entry. The first of these HIV co-receptors to be identified was
"fusin", also known as CXCR4. T-tropic strains of HIV use fusin,
along with the CD4 molecule, for entry into cells.
In recent experiments, Masako Moriuchi, Ph.D., and her colleagues
have cloned the promoter region of the CXCR4 gene, and identified
key elements of the promotor region which begin the process in the
cell of new fusin molecules being synthesized.
"Because increased expression of fusin on immune system cells may
facilitate HIV's replication and spread, a further understanding of the
mechanisms involved in the genetic regulation of fusin expression by
immune system cells may help us more precisely delineate the
pathogenic processes of HIV disease," says Dr. Fauci.
Masako Moriuchi, et al. Cloning and analysis of the promoter region
of CXCR4, a co-receptor for HIV-1 entry. Session 6, Abstract 20,
Thursday, 11:15 a.m.
- NK Cells Are Important Sources of Beta-Chemokines
New findings by Alessandra Oliva, M.D., and her LIR colleagues
demonstrate that natural killer (NK) cells are potent producers of
immune system molecules called beta-chemokines, which inhibit the
replication and spread of certain strains of HIV.
Beta-chemokines include MIP-1alpha, MIP-1beta and RANTES, and
inhibit infection with the strains of HIV most commonly transmitted
from person-to-person, perhaps by competitively occupying or
downregulating co-receptors on immune system cells used by HIV for
fusion and entry.
In cell culture experiments, the researchers found that NK cells
suppressed viral replication to a degree comparable to that previously
observed with CD8+ T cells, another source of beta-chemokines.
"Further delineation of immune system cells and molecules involved
in the regulation of HIV replication will be critical for a more
comprehensive understanding of the mechanisms of HIV disease, as
well as for the design of strategies for potential therapeutic
manipulation of these factors," notes Dr. Fauci.
Alessandra Oliva, et al. Suppression of HIV replication by NK
cell-derived beta-chemokines. Session 6, Abstract 21. Thursday,
- Thalidomide Ineffective in Reducing IL-2-Related
NIAID scientists have shown that treatment with the cytokine
interleukin-2 can significantly raise the CD4+ counts of HIV-infected
patients with baseline counts above 200 cells/mm3 of blood (see New
England Journal of Medicine 1996;335:1350-56). However, IL-2
therapy also is associated with increases in serum levels of tumor
necrosis factor-alpha, which may account for the flu-like symptoms
and transient increases in viral load sometimes seen during IL-2
infusions. Blocking TNF-alpha may provide a way to obviate some of
the undesired effects of IL-2 therapy.
An ongoing randomized, controlled study at NIAID has assessed two
TNF-alpha blockers. One of them, thalidomide, proved ineffective in
blocking either IL-2 related side effects or increases in TNF-alpha at
the maximally tolerated dose of 300 milligrams three times daily, says
Robert Walker, M.D. Thalidomide is useful in other contexts, Dr.
Walker notes, including as a treatment for oral aphthous ulcers
frequently seen in HIV-infected people.
In another arm of the study, an anti-TNF monoclonal antibody has
been well-tolerated by IL-2 patients. Although low doses of the
antibodies have had little effect on IL-2 side effects, higher doses of
this treatment are now being assessed.
Robert Walker, et al. Effects of TNF-alpha antagonists thalidomide
and monoclonal anti-TNF antibody (cA2) on reducing IL-2-associated
toxicities: a randomized, controlled trial. Session 8, Abstract 36.
Thursday, 10:30 a.m.
- IL-10 Study: Transient Reduction in Viral Load Due
to Altered Cytokine Environment and Co-Receptor
In cell culture experiments conducted over the past decade, LIR
scientists have demonstrated that certain cytokines normally secreted
by immune system cells, such as tumor necrosis factor-alpha and
interleukin-6, can boost the replication of HIV. Other cytokines such
as interleukin-10 inhibit HIV replication, in part by blocking the
activity of TNF-alpha and IL-6.
These in vitro experiments have shown that HIV replication is
regulated by a delicate balance between inductive and suppressive
cytokines. Altering this balance can dramatically influence HIV
replication in the test tube and perhaps, new
research suggests, in the body as well.
In a phase I clinical trial at NIAID, Drew Weissman, M.D., Ph.D., and
his colleagues administered a single, low dose of IL-10 to 11
HIV-infected people and found that their bloodstream levels of HIV
dropped by about 70 percent. Virus levels were lowest approximately
12 hours following injection, and returned to baseline about 24 hours
after the IL-10 injection. The investigators
noted no adverse events associated with the injection.
Two observations may help explain the transient drop in virus levels
associated with IL-10 injections, the researchers suggest. First,
following IL-10 injection, patients' immune system cells made
considerably less of the inductive cytokines such as TNF-alpha known
to boost HIV replication. Second, the patients' CD4+ T cells
expressed fewer of the co-receptors that are needed by HIV to bind to
and enter these cells.
"Our findings fortify the concept that the body's own complex network
of cytokines plays a pivotal role in determining the net rate of viral
replication in an HIV-infected individual," says Dr. Weissman. "It
may prove possible to manipulate this network to therapeutic
Drew Weissman, et al. Interleukin-10 decreases HIV plasma viral
load: results of a phase I clinical trial. Session 8, abstract 37.
Thursday, 11:30 a.m.
- IL-10, TGF-Beta Inhibit TB-Induced HIV Replication
Last year, LIR scientists demonstrated that active TB infection boosts
HIV replication in HIV-infected people (see Journal of Immunology
1996;157:1271-1278). This observation helped explain why
HIV-infected people with active TB have a poorer prognosis that
HIV-infected people without TB. The researchers also found that the
TB organism and TB-derived proteins increase HIV replication in the
test tube when added to cells taken from HIV-infected patients.
New in vitro observations, to be presented by Delia Goletti, M.D.,
Ph.D, formerly of LIR and now working in Italy, show that
TB-induced increases in HIV replication are associated with high
levels of pro-inflammatory cytokines such as interleukin-1, tumor
necrosis-alpha and interleukin-6.
Dr. Goletti and colleagues also have found that TB-induced increases
in HIV replication can be blocked in cell culture by adding the
suppressive cytokines interleukin-10 (IL-10) and transforming growth
factor-beta (TGF-beta). The suppressive cytokines appear to inhibit
virus replication by blocking the activity of the pro-inflammatory
cytokines, as well as by diminishing proliferation and activation of
Dr. Goletti and colleagues also have found that small amounts of IL-10
and TGF-beta are induced by TB or TB-derived proteins, in addition to
pro-inflammatory cytokines. When they used antibodies to block this
"endogenous" IL-10 and TGF-beta in cell cultures, they observed an
increase in cellular activation and consequently an elevation of HIV
"The delicate balance between pro-inflammatory and
anti-inflammatory cytokines plays a major role in HIV replication
induced by a common pathogen such as TB," says Dr. Fauci.
Delia Goletti, et al. Exogenous and endogenous anti-inflammatory
cytokines IL-10 and TGF-beta inhibit tuberculosis-induced human
immunodeficiency virus (HIV) replication in CD8-depleted peripheral
blood mononuclear cells from HIV-infected individuals. Session 17,
Abstract 121. Thursday, 4:00 p.m.
- Latently Infected Cells Are A Major Source of Viral Burst After
In a person infected with HIV, activation of the immune system by
immunization or other stimuli results in a short-term increase in the
amount of the virus in the plasma. Where does the new virus come
from -- cells that are already producing virus, or cells that are latently
Mario Ostrowski, M.D., and his colleagues have new data that help
answer this question. They tested tissue samples from the blood and
lymph nodes of an HIV-infected individual, and found that the person
had two distinct "quasispecies" of HIV in his body. Although both
types were found in all the samples tested, one type predominated in
the plasma, the other in the peripheral blood and lymph node
After the patient was given a tetanus shot, levels of virus in the plasma
rose transiently 7.5-fold, reaching a peak after eight days. Now, the
researchers found, the predominant virus type in the plasma was the
quasispecies previously seen mostly in the blood and lymph node
"These findings, in conjunction with other work, suggest that the
increase in viremia following activation of the immune system is a
consequence of mobilization of latently infected CD4+ T cells in the
lymphoid organs, not merely an increase in virus replication in cells
that are already producing virus," says Dr. Fauci.
Mario Ostrowski, et al. Examination of HIV-1 viral quasispecies after
tetanus immunization. Session 17, Abstract 118. Thursday, 4:00 p.m.
- Compound from Dogfish Shark is Potent Inhibitor of HIV
Audrey Kinter and her LIR colleagues have found that MSI-1436, a
compound isolated from the dogfish shark, can dramatically inhibit
HIV replication in the test tube without disrupting CD4+ T cell
proliferation and other normal cellular activities.
MSI-1436 works by blocking a process central to cellular activation --
the exchange of ions across the cell membrane. Previous research by
LIR scientists and others has shown that cellular activation by stimuli
such as opportunistic infections and immunizations boosts HIV
"MSI-1436 and related compounds that interfere with cellular
activation events warrant further testing as possible therapies for the
treatment of HIV-infected individuals," says Ms. Kinter.
Audrey Kinter, et al. MSI-1436, a novel aminosterol, inhibits HIV
replication in vitro and in vivo infected mononuclear cells. Session 25,
Abstract 231. Thursday, 4:00 p.m.
- Loss of CD4+ T Cell Diversity in Late-Stage Disease
Not Reversed by Therapy
In a study of patients whose CD4+ T cell counts dropped from more
than 500 cells/mm3 to under 50 cells/mm3, NIAID researchers found
that certain types, or clones, of CD4+ T cells may be permanently lost
as disease progresses.
Therapies that increase CD4+ T cell numbers, such as interleukin-2
and protease inhibitors, may boost the remaining clones, but appear to
have little effect on the lost cell types.
The findings, says Dr. Fauci, "argue for early intervention before
elements of the immune system are irretrievably lost. In addition,
prophylaxis for opportunistic infections may remain important for
patients who have rising T cell counts but may be missing part of their
Mark Connors et al. HIV induces changes in CD4+ T cell phenotype
and repertoire that are not immediately restored by antiviral or
Session 39, Abstract 369. Friday, 11:00 a.m.
- Cytokine Environment Influences HIV Phenotype
New in vitro data suggest that the presence or absence of certain
cytokines influences the relative rate of replication of different strains
Early in the course of HIV disease, the main strains of HIV found in
HIV-infected people are macrophage-tropic (M-tropic) isolates. As
disease progresses, T-cell line tropic (T-tropic) strains of HIV appear,
coincident with the decline of the immune system. People who have
mostly T-tropic strains of HIV replicating in their bodies are at
considerable risk of disease progression.
M-tropic and T-tropic isolates of HIV also are known as
non-syncytia-inducing (NSI) and syncytia-inducing (SI) strains,
respectively, based on observed differences in their ability to cause the
formation of giant cells called syncytia in cell culture. Recent studies
have shown that NSI (M-tropic) strains, but not SI (T-tropic) strains
are inhibited by immune system molecules called beta-chemokines.
LIR researchers JoAn Monaco, Audrey Kinter and their colleagues
have developed a model system to determine whether the cytokine
microenvironment of HIV-infected cell cultures can be manipulated to
influence the relative replication of NSI and SI strains of HIV.
In certain individuals, they found that either an M-topic or a T-topic
virus was predominant in culture regardless of the conditions of the
culture. However, in certain individuals, the propagation of one or the
other type of virus was dependent on the culture conditions. For
example, in certain experiments they added the cytokines IL-2 and
IL-4 to cells taken from HIV-infected people. They found that virus
subsequently isolated from these cells could be suppressed for
prolonged periods by beta-chemokines, suggesting that IL-2 and IL-4
had selected for NSI variant replication. In contrast, virus from cells
treated with IL-2 and a mitogen, but not with IL-4, rapidly became
insensitive to beta-chemokines, suggesting that SI variant replication
had been selected.
Ongoing studies with the model system are assessing the effects of
other cytokines on the relative replication of NSI and SI HIV strains.
"Understanding the conditions that regulate the replication of different
strains of HIV in a person's body, including the cytokine
microenvironment in lymph nodes and other organs, may provide new
leads for therapeutic strategies for HIV-infected people," says Dr.
JoAn Monaco, et al. Cytokine/chemokine-mediated regulation of in
vitro predominance of SI versus NSI HIV replication in PBMC from
HIV-infected subjects. Session 51, Abstract 442. Friday, 4:00 p.m.
- Monocyte/Macrophage Resistance to T-tropic HIV
Strains Due to Alterations in Fusin
Hiroyuki Moriuchi, M.D., and his colleague have provided a likely
explanation for a seemingly paradoxical phenomenon:
monocyte/macrophage (M/M) cells express fusin, yet generally are
resistant to T-tropic strains of the virus.
Their research suggests that although M/M cells make fusin, the
molecule is altered on its way to the cell surface. The modified form
of fusin binds T-tropic strains of HIV poorly; hence, these viruses are
unable to establish a foothold and enter the cell.
"This research confirms what made sense to us intuitively: that
resistance to infection of monocyte/macrophages by T-tropic strains of
HIV occurs at the level of fusion and entry," says Dr. Fauci.
Hiroyuki Moriuchi et al. Resistance to infection of promonocytic U937
subclones with T cell-tropic HIV-1 occurs at the level of fusion/entry.
Session 51, Abstract 446. Friday, 4:00 p.m.
- Dendritic Cells Have Multiple Co-Receptors for HIV Entry
Dendritic cells, the first cells infected by HIV when a person is
exposed to the virus during sex, carry the virus from the site of
infection to the lymph nodes and other organs, where CD4+ T cells
become infected in large numbers.
Because of their importance to the initial events in HIV disease,
dendritic cells have been a focus of LIR research. One important LIR
project has focused on the co-receptors on dendritic cells used by HIV
(in addition to the primary HIV receptor, CD4) to enter the cell.
In recent experiments, Andrea Rubbert, M.D., and her colleagues have
shown that dendritic cells have multiple HIV co-receptors. Among
these co-receptors are CCR3, which normally binds to an immune
system molecule called eotaxin, and a previously unrecognized
receptor that binds a signalling molecule called stromal cell-derived
factor 1 (SDF-1). Interestingly, another known HIV co-receptor called
fusin or CXCR4, which also binds SDF-1, was not found on the
surface of dendritic cells.
"Further understanding of the complexity of co-receptor expression by
dendritic cells will be important to understanding the pathogenesis of
HIV infection, and may suggest new targets for drug and vaccine
development," says Dr. Fauci.
Andrea Rubbert, et al. Dendritic cells express and use multiple
co-receptors for HIV entry. Session 88, Abstract LB16. Sunday,
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