Download Allergen-Like gp120 Molecules from HIV

Allergen-Like gp120 Molecules from
HIV-1 Account for AIDS
CpG oligodeoxynucleotides may counteract the usual response to gp
120 by reactivating adaptive immunity and inhibiting HIV-1 replication
Yechiel Becker
ore than 40 million people
throughout the world have been
infected with the human immunodeficiency virus-1 (HIV-1), and the
virus continues to spread, causing
15,000 new infections per day. Many of those
who become infected with this virus develop
acquired immune deficiency syndrome, or
AIDS, despite efforts to prevent those infections
or to treat the infected with intensive antiviral
therapies.
HIV-1 was first isolated in 1983 from a patient from East Africa by a team from the Pasteur Institute in Paris, France. An analysis of the
viral RNA genome and proteins led to the development of tests that determined that HIV-1 is a
human lentivirus. Consequently, treatment
strategies tend to focus on antiviral drugs with
the ability to inhibit HIV-1, while preventive
strategies look toward development of a vaccine
to immunize populations in high-risk zones.
Currently, the most prevalent treatment approach involves a regime known as highly active
antiretroviral therapy (HAART), in which patients are administered several agents that block
HIV replication by blocking its reverse transcriptase and proteinase. Although this regime
has prolonged the lives of many HIV-1 patients,
drug-resistant mutant viruses continue to emerge.
Meanwhile, despite efforts to formulate vaccines based on the HIV glycoprotein gp120,
those candidate vaccines fail to protect recipients against HIV-1 infections when tested in
large-scale human trials. Even after 20 years of
active research on HIV-1/AIDS, many of the
reasons behind such vaccine failures and, indeed, behind the broader immunodeficiency as-
M
sociated with this virus are yet to be deciphered.
Thus, a new approach to addressing these problems appears to be needed.
HIV-1 Follows a Four-Step Mode
after Entering a New Host
HIV-1 surfaced in East African populations
about 60 –100 years ago, reflecting human exposure to the chimpanzee lentivirus simian immunodeficiency virus (SIV), which circulates in
the blood of such animals. In contrast to SIV,
when HIV-1 infects humans, it can be transmitted from one individual to another by means of
free and T cell-associated virions in semen and
blood.
Overall, HIV-1 follows four distinct steps
during which it overcomes adaptive immunity
of individuals whom it infects:
• HIV-1 infected T cells arriving at the portal of
virus entry encounter dendritic cells (Fig. 1A).
• “Veiled” cells arriving at the T cell compartment of draining lymph nodes present viral
antigens to naive T cells (Fig. 1B). Polarized
Th1 cells activate CTL precursors to become
antiviral CTLs. Th2 cells induce B cells to
synthesize antiviral antibodies (Fig. 1C).
• HIV-1 establishes foci of virion production,
shedding gp120 molecules that damage vital
organs and cause AIDS (Fig. 2A, B, and C).
• Shed allergen-like gp120 molecules induce hematopoietic cells to release IL-4, enhancing
viral replication and inhibiting adaptive immunity (Fig. 2D, E, and F).
Upon entering the body, HIV-1 virions encoun-
Yechiel Becker is a
professor in the
Department of Molecular Virology,
Faculty of Medicine, at the Hebrew
University of
Jerusalem, Jerusalem, Israel.
[email protected].
Volume 70, Number 12, 2004 / ASM News Y 565
FIGURE 1
The antiviral adaptive immune response during primary infection (0-6 months postinfection).
ter Langerhans cells (LCs), dendritic cells (DCs),
and monocyte-derived DCs that are part of the
innate defenses against microbial infections. After engulfing the virions, the LCs and DCs migrate to the lymph nodes, where they present the
viral antigens to naive T cells, inducing host
adaptive immune responses. LCs and DCs are
armed with a large number of lectin receptors,
which bind pathogens that express mannoserich glycans.
The viral gp160 glycoprotein molecules that
are anchored in the envelopes of virions consist
of two components: a membrane-anchored
gp41 protein and a gp120 protein that bind to
one another noncovalently. The N-terminus of
gp41 contains the fusion domain, while the
566 Y ASM News / Volume 70, Number 12, 2004
gp120 protein contains domains for attaching to
CD4 and CCR5 receptors on host T cells. Both
gp41 and gp120 proteins are heavily glycosylated with mannose-rich glycans. At the portal
of virus entry, the lining epithelial cells also
express lectin receptors to which the virions
attach via their glycosylated gp120 molecules.
LCs and DCs bring virions into their cytoplasms through endocytosis. Those virions then
are transported to compartments and are degraded into peptides and glycopeptides before
being loaded onto human leukocyte antigens
(HLA) class I, class II, and CD1 molecules. A
fraction of the virions, most likely those that are
bound instead to cholesterol receptors, remain
intact and retain their infectivity.
FIGURE 2
The antiviral adaptive immune response during primary infection (6 months to 6 years postinfection).
Meanwhile, the virus-loaded DCs migrate to
lymph nodes. After binding virions, the DCs
contract their dendrites and transform into
round cells with “sails,” that are also known as
“veiled” cells. These cells navigate the lymph
stream through the lymph nodes that drain the
tissue at the portal of virus entry. The migration
of the veiled cells to the lymph nodes takes 24
hours. During that period, the virions are proteolytically degraded in the HLA class II compartment and by the cytoplasmic proteasomes,
loading the HLA class I molecules in the endoplasmic reticulum. The viral lipids and glycolipids are loaded into CD-1 molecules that resemble HLA-class I molecules. These processes are
completed by the time the “veiled” cells reach
those lymph nodes.
“Veiled” Cells Present HIV
Antigens to Naive T Cells
The arrival of “veiled” cells at the compartments of T cells located in lymph nodes constitutes a major event for naive T cells, which
travel to those nodes from the thymus with the
capacity to distinguish between cellular and foreign antigens.
Upon arriving at the lymph node, DCs extend
their dendrites, which are loaded with arrays of
HLA class I, class II, and CD1 molecules, as well as
other cellular receptors. The naive T cells attach to
the HLA class I, CD1, and class II molecules and
sample HIV-1 antigens with their receptors. After
a short binding period, the T cells detach but after
Volume 70, Number 12, 2004 / ASM News Y 567
several hours return to the same type of HLA
molecules for a longer attachment period.
The cells require nearly 24 hours to establish
their identity as T helper 1 (Th1) cells (after
binding to HLA class I molecules) and as T
helper 2 (Th2) cells (after binding to HLA class
II molecules). Th1 cells are equipped with information that enables them to present manifold
viral antigens to cytotoxic T cell (CTL) precursors, which develop into antiviral CTLs. Meanwhile, Th2 polarized cells migrate to the B cell
compartment and instruct B cells to synthesize
antiviral IgG antibodies. The polarization of the
T cells is associated with their ability to release
Th1 (interleukin-2 and -12 [IL-2, IL-12]) or Th2
(IL-4, IL-5, IL-10, IL-13) cytokines.
Following the synthesis of IL-4 cytokines by
polarized Th2 cells, residual HIV-1 virions infect the polarized Th2 cells and establish foci of
virus production in lymph nodes. These virions
use two envelope gp120 amino acid domains for
binding to CD4 molecules (main receptors) and
to the CCR5 chemokine receptors (coreceptors)
that are present on lipid rafts within the Th2
cellular plasma membrane. After binding, the
gp120 molecules are shed and the gp41 protein
fusion sequence is introduced into the Th2
plasma membrane.
The fusion of the viral envelope and the cell
plasma membrane enables the viral capsid to
enter the Th2 cell cytoplasm. After uncoating,
the viral RNA molecules form a prereplication
complex that is transported into the cell nucleus,
and the newly synthesized viral genome-encoding DNA is integrated into the cellular DNA.
Shed gp120 Molecules Damage
Organs, Cause AIDS
At the outset of an HIV-1 infection, only small
numbers of Th2 cells are infected, and the adaptive immunity of the individual remains fully
functional. Thus, polarized Th1 cells induce the
antiviral cellular (CTLs) response while Th2
cells induce B cells to synthesize antiviral antibodies (Fig. 1A). For the next five to six months,
the host adaptive immune response successfully
reduces virion levels in the blood. However,
glycan chains that partly conceal neutralization
domains on the virion gp120 molecules protect
some number of virions from antiviral antibodies. Meanwhile, antiviral CTLs are more effective at killing virus-infected cells and thus clear-
568 Y ASM News / Volume 70, Number 12, 2004
ing the virus during the five- to six-month period
immediately following infection. During this period, however, viral gp120 molecules being shed
from virions trigger events that lead the adaptive
immune system to become less and less effective
and, ultimately, paralyzed.
How does HIV-1 interfere with the host immune system to keep it from working effectively?
HIV-1-infected Th2 cells produce a large number
of virions that shed most of their gp120 molecules
into the blood (Fig. 2B). Gradual increases of IL-4
and IgE levels in the blood of HIV-1-infected individuals are telltale signs of the onset of AIDS.
Curiously, environmental allergens also induce a gradual increase of IL-4 and IgE levels in
the blood of individuals with allergies. Moreover, both environmental and endogenous allergen proteins contain a superantigen (superallergen) domain, which enables them to bind to IgE
molecules that are bound to Fc⑀RI⫹ hematopoietic cells, including basophils, mast cells, monocytes, and DCs. When allergens bind to the IgE
VH3 domain, they trigger hematopoietic cells to
release large amounts of IL-4, an inhibitor of
Th1 cell cytokine synthesis and an inducer of
IgE synthesis by B cells.
Furthermore, HIV-1 gp120 molecules contain
a superantigen domain that binds to the VH3
sequence of IgE molecules that are bound to
Fc⑀RI⫹ hematopoietic cells. Purified HIV-1
gp120 molecules and human endogenous allergens bind with their superantigen domains to
IgE/Fc⑀RI⫹ hematopoietic cells (basophils) and
induce them to synthesize and release large
amounts of IL-4 (Fig.2C).
These remarkable similarities in the way allergens and HIV-1 gp120 behave at the cellular
level suggest that HIV-1-associated AIDS is a
severe form of allergy and that the principal
viral allergen is gp120.
gp120 molecules Induce Release of IL-4,
Inhibiting Adaptive Immunity
Healthy individuals maintain their Th1-Th2 cytokine balance by controlling Th1 and Th2 cytokine levels. Th1 cells synthesize IL-2 and IL-12
cytokines that activate precursor CTLs, while
Th2 cells release IL-4, IL-5, IL-10, and IL-13, of
which IL-4 induces B cells to synthesize immunoglobulins—primarily IgG but also IgE and IgA.
However, when an individual is infected with
HIV-1, the allergen-like gp120 shatters the
usual Th1-Th2 equilibrium, leading
FIGURE 3
IL-4 levels to increase while inhibiting
the synthesis of Th1 cytokines and CTL
precursors, and thus interfering with the
ordinary functions of the host adaptive
immune system (Fig. 2D). Increased levels of IL-4 are responsible for inhibiting
IgG synthesis by B cells and activating IgE
synthesis. There are higher levels of IgE
molecules in the serum, enabling them to
bind to greater numbers of Fc⑀RI⫹ hematopoietic cells, which bind gp120 and accelerate the synthesis and release of IL-4
(Fig. 2E).
In the presence of IL-4, HIV-1-infected
Th2 cells down-regulate expression of coreceptor CCR5, to which slow-replicating virions bind, but up-regulate coreceptor CXCR4, to which fast-replicating
HIV-1 strains bind. These changes further enhance production of HIV-1.
Within 5 to 6 months after an individual
is infected with HIV-1, adaptive immune
responses more or less shut down, leaving
the individual highly vulnerable to other
infectious agents. Meanwhile, HIV-1
continues to replicate, producing more
and more virions that shed additional
gp120 molecules.
HIV-1 continues to cause further
damage to such patients by affecting
other organ systems. For example, glycosylated gp120 molecules in the blood
are carried into the microvascular sysPredicted effects of CpG ODNs-induced synthesis of INF-␣, IFN-␤ on HIV/AIDS patients.
tem of the brain, often referred to as the
blood-brain barrier. Endothelial cells in
these blood vessels express lectin receptors that can bind gp120 molecules and may
proach could entail inducing specific host cells
transfer them to neurons, where they can give rise
to make and release molecules that inhibit IL-4
to dementia. Similarly, gp120 molecules may
synthesis and HIV-1 replication. Such changes
damage other organs, such as the heart, kidney,
would be expected, in turn, to reactivate the
and liver, that may hasten an infected individual’s
adaptive immune system. Recent studies on the
demise (Fig. 2F).
10 human Toll-like receptors (TLRs) reveal that
plasmacytoid DCs (pDCs) and B cells express
TLR9. Both unmethylated bacterial DNA and
CpG Treatment Reactivates Adaptive
synthetic CpG oliogodoxynucleotides (ODN)
Immunity of HIV-1/AIDS Patients
bind to the TLR9 receptor. When CpG ODN
Because HIV-1 and allergens employ the same
binds to TLR9⫹ on pDCs, they are induced to
synthesize and release large amounts of interfermechanism for inducing IL-4 synthesis, it stands
ons (IFN) ␣, and ␤, which can inhibit IL-4
to reason that inhibiting IL-4 synthesis and resynthesis by Fc⑀RI⫹ hematopoietic cells and
activating Th1 cytokine synthesis—the Th23
HIV-1 replication in Th2 cells. Meanwhile, CpG
Th1 reversion hypothesis— could prove a valid
ODN binding to TLR9⫹ leads B cells to stop
approach for treating HIV-1/AIDS. This ap-
Volume 70, Number 12, 2004 / ASM News Y 569
producing IgE and to start making IgG. Treating
Th1 cells with IFNs leads those cells to produce
cytokines that activate CTL precursors.
Proposal for Treating HIV-1-AIDS Patients
We propose treating HIV-1/AIDS patients with
CpG ODN to reactivate their damaged immune
systems and trigger a vigorous antiviral response
(Fig. 3). The presence of viral proteins in HIV-1infected individuals should enable DCs of the innate system to present viral antigens to Th1 and
Th2 cells, which will then direct the reactivated
cellular and humoral adaptive immune systems to
clear residual virus and protect against reinfection.
Overproducing IFN-␣, which can lead to apoptosis of cells, is believed to induce autoantibody
synthesis. However, inducing IL-10 down-regulates synthesis of IFN-␣.
If effective for treating individuals with HIV-1/
AIDS, relatively simple and inexpensive agents
such as CpG ODN could help in controlling this
pandemic, especially in high-risk regions throughout the developing world where resources for
combating this and other diseases are so scarce.
ACKNOWLEDGMENTS
Special thanks are due to Professor G. Darai of the Hygiene Institute at Karl-Ruprecht University in Heidelberg, Germany for
his advice and support. Mr. Avi Aronsky is to be commended for his excellent technical assistance, as is Mr. Aviad Levin for
the design of the figures. The study was supported by the Foundation for Molecular Virology and Cell Biology, Phoenix, Ariz.,
United States of America.
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