What specific cells are infected with HIV-1 and how is this accomplished (specific viral ligands and host receptors)?

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 sociated with this virus are yet to be deciphered.


M throughout the world have been
infected with the human immuno-
deficiency virus-1 (HIV-1), and the
virus continues to spread, causing
Thus, a new approach to addressing these prob-
lems appears to be needed.


15,000 new infections per day. Many of those HIV-1 Follows a Four-Step Mode
who become infected with this virus develop after Entering a New Host
acquired immune deficiency syndrome, or
AIDS, despite efforts to prevent those infections HIV-1 surfaced in East African populations
or to treat the infected with intensive antiviral about 60 ­100 years ago, reflecting human ex-
therapies. posure to the chimpanzee lentivirus simian im-
HIV-1 was first isolated in 1983 from a pa- munodeficiency virus (SIV), which circulates in
tient from East Africa by a team from the Pas- the blood of such animals. In contrast to SIV,
teur Institute in Paris, France. An analysis of the when HIV-1 infects humans, it can be transmit-
viral RNA genome and proteins led to the devel- ted from one individual to another by means of
opment of tests that determined that HIV-1 is a free and T cell-associated virions in semen and
human lentivirus. Consequently, treatment blood.
Overall, HIV-1 follows four distinct steps
strategies tend to focus on antiviral drugs with
during which it overcomes adaptive immunity
the ability to inhibit HIV-1, while preventive
of individuals whom it infects:
strategies look toward development of a vaccine
to immunize populations in high-risk zones. · HIV-1 infected T cells arriving at the portal of
Currently, the most prevalent treatment ap- virus entry encounter dendritic cells (Fig. 1A).
proach involves a regime known as highly active · "Veiled" cells arriving at the T cell compart-
antiretroviral therapy (HAART), in which pa- ment of draining lymph nodes present viral
tients are administered several agents that block antigens to naive T cells (Fig. 1B). Polarized
HIV replication by blocking its reverse tran- Th1 cells activate CTL precursors to become
scriptase and proteinase. Although this regime antiviral CTLs. Th2 cells induce B cells to
has prolonged the lives of many HIV-1 patients, synthesize antiviral antibodies (Fig. 1C). Yechiel Becker is a
drug-resistant mutant viruses continue to emerge.
· HIV-1 establishes foci of virion production, professor in the
Meanwhile, despite efforts to formulate vac- Department of Mo-
shedding gp120 molecules that damage vital
cines based on the HIV glycoprotein gp120, lecular Virology,
organs and cause AIDS (Fig. 2A, B, and C).
those candidate vaccines fail to protect recipi- Faculty of Medi-
ents against HIV-1 infections when tested in · Shed allergen-like gp120 molecules induce he-
cine, at the Hebrew
large-scale human trials. Even after 20 years of matopoietic cells to release IL-4, enhancing
University of
active research on HIV-1/AIDS, many of the viral replication and inhibiting adaptive im-
Jerusalem, Jerusa-
reasons behind such vaccine failures and, in- munity (Fig. 2D, E, and F).
lem, Israel.
deed, behind the broader immunodeficiency as- Upon entering the body, HIV-1 virions encoun- becker@md.huji.ac.il.




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), gp120 protein contains domains for attaching to
and monocyte-derived DCs that are part of the CD4 and CCR5 receptors on host T cells. Both
innate defenses against microbial infections. Af- gp41 and gp120 proteins are heavily glycosy-
ter engulfing the virions, the LCs and DCs mi- lated with mannose-rich glycans. At the portal
grate to the lymph nodes, where they present the of virus entry, the lining epithelial cells also
viral antigens to naive T cells, inducing host express lectin receptors to which the virions
adaptive immune responses. LCs and DCs are attach via their glycosylated gp120 molecules.
armed with a large number of lectin receptors, LCs and DCs bring virions into their cyto-
which bind pathogens that express mannose- plasms through endocytosis. Those virions then
rich glycans. are transported to compartments and are de-
The viral gp160 glycoprotein molecules that graded into peptides and glycopeptides before
are anchored in the envelopes of virions consist being loaded onto human leukocyte antigens
of two components: a membrane-anchored (HLA) class I, class II, and CD1 molecules. A
gp41 protein and a gp120 protein that bind to fraction of the virions, most likely those that are
one another noncovalently. The N-terminus of bound instead to cholesterol receptors, remain
gp41 contains the fusion domain, while the intact and retain their infectivity.



566 Y ASM News / Volume 70, Number 12, 2004
FIGURE 2




The antiviral adaptive immune response during primary infection (6 months to 6 years postinfection).



Meanwhile, the virus-loaded DCs migrate to "Veiled" Cells Present HIV
lymph nodes. After binding virions, the DCs Antigens to Naive T Cells
contract their dendrites and transform into
round cells with "sails," that are also known as
The arrival of "veiled" cells at the compart-
"veiled" cells. These cells navigate the lymph
ments of T cells located in lymph nodes consti-
stream through the lymph nodes that drain the
tissue at the portal of virus entry. The migration tutes a major event for naive T cells, which
of the veiled cells to the lymph nodes takes 24 travel to those nodes from the thymus with the
hours. During that period, the virions are pro- capacity to distinguish between cellular and for-
teolytically degraded in the HLA class II com- eign antigens.
partment and by the cytoplasmic proteasomes, Upon arriving at the lymph node, DCs extend
loading the HLA class I molecules in the endo- their dendrites, which are loaded with arrays of
plasmic reticulum. The viral lipids and glycolip- HLA class I, class II, and CD1 molecules, as well as
ids are loaded into CD-1 molecules that resem- other cellular receptors. The naive T cells attach to
ble HLA-class I molecules. These processes are the HLA class I, CD1, and class II molecules and
completed by the time the "veiled" cells reach sample HIV-1 antigens with their receptors. After
those lymph nodes. 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 ing the virus during the five- to six-month period
molecules for a longer attachment period. immediately following infection. During this pe-
The cells require nearly 24 hours to establish riod, however, viral gp120 molecules being shed
their identity as T helper 1 (Th1) cells (after from virions trigger events that lead the adaptive
binding to HLA class I molecules) and as T immune system to become less and less effective
helper 2 (Th2) cells (after binding to HLA class and, ultimately, paralyzed.
II molecules). Th1 cells are equipped with infor- How does HIV-1 interfere with the host im-
mation that enables them to present manifold mune system to keep it from working effectively?
viral antigens to cytotoxic T cell (CTL) precur- HIV-1-infected Th2 cells produce a large number
sors, which develop into antiviral CTLs. Mean- of virions that shed most of their gp120 molecules
while, Th2 polarized cells migrate to the B cell into the blood (Fig. 2B). Gradual increases of IL-4
compartment and instruct B cells to synthesize and IgE levels in the blood of HIV-1-infected indi-
antiviral IgG antibodies. The polarization of the viduals are telltale signs of the onset of AIDS.
T cells is associated with their ability to release Curiously, environmental allergens also in-
Th1 (interleukin-2 and -12 [IL-2, IL-12]) or Th2 duce a gradual increase of IL-4 and IgE levels in
(IL-4, IL-5, IL-10, IL-13) cytokines. the blood of individuals with allergies. More-
Following the synthesis of IL-4 cytokines by over, both environmental and endogenous aller-
polarized Th2 cells, residual HIV-1 virions in- gen proteins contain a superantigen (superaller-
fect the polarized Th2 cells and establish foci of gen) domain, which enables them to bind to IgE
virus production in lymph nodes. These virions molecules that are bound to Fc RI hematopoi-
use two envelope gp120 amino acid domains for etic cells, including basophils, mast cells, mono-
binding to CD4 molecules (main receptors) and cytes, and DCs. When allergens bind to the IgE
to the CCR5 chemokine receptors (coreceptors) VH3 domain, they trigger hematopoietic cells to
that are present on lipid rafts within the Th2 release large amounts of IL-4, an inhibitor of
cellular plasma membrane. After binding, the Th1 cell cytokine synthesis and an inducer of
gp120 molecules are shed and the gp41 protein IgE synthesis by B cells.
fusion sequence is introduced into the Th2 Furthermore, HIV-1 gp120 molecules contain
plasma membrane. a superantigen domain that binds to the VH3
The fusion of the viral envelope and the cell sequence of IgE molecules that are bound to
plasma membrane enables the viral capsid to Fc RI hematopoietic cells. Purified HIV-1
enter the Th2 cell cytoplasm. After uncoating, gp120 molecules and human endogenous aller-
the viral RNA molecules form a prereplication gens bind with their superantigen domains to
complex that is transported into the cell nucleus, IgE/Fc RI hematopoietic cells (basophils) and
and the newly synthesized viral genome-encod- induce them to synthesize and release large
ing DNA is integrated into the cellular DNA. amounts of IL-4 (Fig.2C).
These remarkable similarities in the way aller-
gens and HIV-1 gp120 behave at the cellular
Shed gp120 Molecules Damage
level suggest that HIV-1-associated AIDS is a
Organs, Cause AIDS
severe form of allergy and that the principal
At the outset of an HIV-1 infection, only small viral allergen is gp120.
numbers of Th2 cells are infected, and the adap-
tive immunity of the individual remains fully
gp120 molecules Induce Release of IL-4,
functional. Thus, polarized Th1 cells induce the
Inhibiting Adaptive Immunity
antiviral cellular (CTLs) response while Th2
cells induce B cells to synthesize antiviral anti- Healthy individuals maintain their Th1-Th2 cy-
bodies (Fig. 1A). For the next five to six months, tokine balance by controlling Th1 and Th2 cy-
the host adaptive immune response successfully tokine levels. Th1 cells synthesize IL-2 and IL-12
reduces virion levels in the blood. However, cytokines that activate precursor CTLs, while
glycan chains that partly conceal neutralization Th2 cells release IL-4, IL-5, IL-10, and IL-13, of
domains on the virion gp120 molecules protect which IL-4 induces B cells to synthesize immu-
some number of virions from antiviral antibod- noglobulins--primarily IgG but also IgE and IgA.
ies. Meanwhile, antiviral CTLs are more effec- However, when an individual is infected with
tive at killing virus-infected cells and thus clear- HIV-1, the allergen-like gp120 shatters the



568 Y ASM News / Volume 70, Number 12, 2004
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 lev-
els 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 hema-
topoietic cells, which bind gp120 and ac-
celerate the synthesis and release of IL-4
(Fig. 2E).
In the presence of IL-4, HIV-1-infected
Th2 cells down-regulate expression of co-
receptor CCR5, to which slow-replicat-
ing virions bind, but up-regulate corecep-
tor CXCR4, to which fast-replicating
HIV-1 strains bind. These changes fur-
ther 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, gly-
cosylated gp120 molecules in the blood
are carried into the microvascular sys-
Predicted 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 recep-
tors 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
mechanism for inducing IL-4 synthesis, it stands synthesize and release large amounts of interfer-
to reason that inhibiting IL-4 synthesis and re- ons (IFN) , and , which can inhibit IL-4
activating Th1 cytokine synthesis--the Th23 synthesis by Fc RI hematopoietic cells and
Th1 reversion hypothesis-- could prove a valid HIV-1 replication in Th2 cells. Meanwhile, CpG
approach for treating HIV-1/AIDS. This ap- ODN binding to TLR9 leads B cells to stop



Volume 70, Number 12, 2004 / ASM News Y 569
producing IgE and to start making IgG. Treating cellular and humoral adaptive immune systems to
Th1 cells with IFNs leads those cells to produce clear residual virus and protect against reinfection.
cytokines that activate CTL precursors. Overproducing IFN- , which can lead to apopto-
sis of cells, is believed to induce autoantibody
Proposal for Treating HIV-1-AIDS Patients synthesis. However, inducing IL-10 down-regu-
We propose treating HIV-1/AIDS patients with lates synthesis of IFN- .
CpG ODN to reactivate their damaged immune If effective for treating individuals with HIV-1/
systems and trigger a vigorous antiviral response AIDS, relatively simple and inexpensive agents
(Fig. 3). The presence of viral proteins in HIV-1- such as CpG ODN could help in controlling this
infected individuals should enable DCs of the in- pandemic, especially in high-risk regions through-
nate system to present viral antigens to Th1 and out the developing world where resources for
Th2 cells, which will then direct the reactivated 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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