Current
Natural Immunity Against HIV Infection
Executive Editors: Marie-Lise Gougeon/Gianfranco Pancino/Fabrizio
Poccia
The Cytokine Network in HIV Infection Pp.677-689
M.
Alfano and G. Poli
Chemokines as Natural HIV Antagonists Pp.691-702
A.
Verani and P. Lusso
Complement Receptors in HIV Infection Pp.703-711
S.
Doepper, L. Kacani, B. Falkensammer, M.P. Dierich and H. Stoiber
Endogenous Inhibitors of HIV: Potent Anti-HIV
Activity of Leukemia Inhibitory Factor Pp.713-722
B.K.
Patterson, A. Tjernlund and J. Andersson
Macrophage Activation and HIV Infection: Can
the Trojan Horse Turn into a Fortress? Pp.723-738
G.
Herbein, A. Coaquette, D. Perez-Bercoff and G. Pancino
Dendritic Cells in Innate Immune Responses
Against HIV Pp.739-756
C.
Servet, L. Zitvogel and A. Hosmalin
NK Cells and HIV Infection: Lessons from
other Viruses Pp.757-768
D.S. Algara and P. Paul
Innate T-Cell Immunity in HIV Infections: The
Role of Vg9Vd2
T Lymphocytes Pp.769-781
F.
Poccia, M.-L. Gougeon, C. Agrati, C. Montesano, F. Martini, C.D. Pauza, P.
Fisch, M. Wallace and M. Malkovsky
[Back to top] The Cytokine Network in HIV Infection
M.
Alfano and G. Poli
Cytokines are
major controller of HIV replication and represent, at the same time, a target
for viral-induced immune dysregulation. This mutual relationship has profound
implications for both active HIV replication and immune-mediated governance of
latency; in addition, cytokines have therapeutic value in the perspective of
immune reconstitution. In the current article we will review the most relevant
aspects emerged in almost 20 years of research in this area with particular
reference to the distinct, but interconnected contribution of the most simple
(cell lines) to the most complex (animal) models of HIV infection.
[Back to top] Chemokines as Natural HIV Antagonists
A.
Verani and P. Lusso
The unexpected
encounter between the fields of HIV and chemokines has opened new perspectives
for understanding the mechanisms of AIDS pathogenesis, as well as for the
development of effective therapies and vaccines. Selected chemokines act as
potent natural inhibitors of HIV infection, as they bind and downmodulate
chemokine receptors that serve as critical coreceptors for HIV to gain access
into cells. The differential usage of the two major HIV coreceptors, CCR5 and
CXCR4, determines the biological diversity among HIV variants. Most primary HIV
strains use CCR5 as a coreceptor and thereby are sensitive to inhibition by the
CCR5-ligand chemokines, RANTES, MIP-1α and MIP-1β. The high level of expression
of these proinflammatory chemokines in HIV-infected secondary lymphoid tissues
may help to explain the inherently slow course of HIV disease. The crucial role
played by CCR5 in the physiology of HIV infection is further attested by the
near-complete resistance to HIV infection in people carrying a homozygous 32bp
deletion within the CCR5 gene (CCR5-.32). A smaller proportion of HIV isolates,
commonly emerging in concomitance with the clinical progression toward AIDS,
uses CXCR4 as a coreceptor and is inhibited by the CXCR4 ligand, SDF-1. The
high level of expresion of SDF-1 in the genital mucosa may help to explain the
inefficient transmission of CXCR4-tropic HIV. Although chemokines or derivative
molecules could be exploited as therapeutic agents against HIV, the risk of
inducing inflammatory side-effects or of interfering with the physiology of the
homeostatic chemokine system represents a potential limitation. However, the
ability of chemokines to block HIV infection can be uncoupled from their
receptor-mediated signaling activity, thus providing a theoretical foundation
for the rational design of safe and effective chemokine receptor inhibitors.
[Back to top] Complement Receptors in HIV Infection
S.
Doepper, L. Kacani, B. Falkensammer, M.P. Dierich and H. Stoiber
Similar to other
pathogens, HIV can directly activate the complement pathway even in the absence
of antibodies. During and after seroconversion, HIV-specific antibodies enhance
the activation of complement and increase deposition of complement fragments on
virions dramatically. However, even in the presence of HIV-specific antibodies,
no or only poor lysis occurs. HIV has adapted different protection mechanisms
to keep complement activation under the threshold necessary to induce virolysis.
In addition to its own envelope proteins, the viral envelope contains
membrane-anchored host molecules. Among those are complement regulatory
proteins that remain functionally active on the surface of HIV and turn down
the complement cascade. In addition, serum proteins with complement regulatory
activities become secondarily attached onto the virus, thereby enhancing the
protection of HIV against complement-mediated damage. Therefore, opsonised
virions accumulate in HIV-infected individuals, which subsequently interact
with complement receptor (CR) expressing cells. This review is mainly focused
on these interactions, which result either in infection of CR-positive cells
with high efficiency, or retention of viral particles on their surface via CRs,
thereby promoting transmission of virus to other permissive cells.
[Back to top] Endogenous Inhibitors of HIV: Potent
Anti-HIV Activity of Leukemia Inhibitory Factor
B.K.
Patterson, A. Tjernlund and J. Andersson
The correlates of
protective immunity in HIV-1 infection include the endogenous production of
compounds with anti-HIV-1 activity. These compounds can be produced
independently of specific humoral or cellular immune responses. A model of
compartmental inhibition of HIV-1 infection is the placenta, an organ that
prevents transmission of HIV-1 to the fetus in the majority of HIV-1
pregnancies. Studies of this organ elucidated new compounds and mechanisms for
prevention and treatment of HIV including the potent inhibitor of HIV-1,
leukemia inhibitory factor (LIF).
Besides
coordinating the humoral and cellular immune responses, cytokines such as IFN-ã
exhibit intrinsic antiviral activity that represents the first line of defense
against pathogens prior to the development of a specific immune response. The
study of antiviral factors is particularly important in HIV/AIDS because of the
direct destruction of the immune system by HIV-1. In this report, we focus on
the identification and mechanism of endogenously produced anti-HIV factors and
the overall function of these factors in the prevention and treatment of
HIV/AIDS.
[Back to top] Macrophage Activation and HIV Infection: Can
the Trojan Horse Turn into a Fortress?
G. Herbein, A. Coaquette, D. Perez-Bercoff and G. Pancino
Macrophages are
infected early during HIV infection and are thought to play the role of a
Trojan horse by spreading infection in tissues. Most recent studies point out to
a more complex role for macrophages in HIV infection: macrophages could
contribute to both host defense and viral persistence and pathogenesis.
Infected macrophages are a reservoir for HIV and modulate apoptosis of T cells
present in their vicinity. Also, a functional impairment of HIV-infected
macrophages may play a role in AIDS pathogenesis. Nevertheless, both activation
and differentiation of monocyte/ macrophages can interfere with susceptibility
of these cells to infection. Therefore, a wide variety of stimuli result in HIV
suppression through macrophage activation. At present times, a dynamic view on
the role of macrophages in HIV infection arises which indicates that
macrophages are a target for the virus and at the same time regulate its
replication. Therefore, macrophages are at the cross-road between protection
and pathogenesis in HIV infection due to their involvement both as a viral
target and a key modulator of non-specific and specific immune responses.
Future studies will help unravel the cellular and molecular mechanisms that
underlie HIV-macrophage interactions and might result in new vaccine and/or
therapeutic strategies.
[Back to top] Dendritic Cells in Innate Immune Responses
Against HIV
C.
Servet, L. Zitvogel and A. Hosmalin
Dendritic cells
(DCs) were recently found to be innate immunity effectors against tumoral cells
and viruses. (i) In response to most viruses, including HIV, plasmacytoid DCs
are responsible for most of the type I IFN secretion, which is strongly
anti-viral and induces TH1 type responses. Myeloid DCs secrete IL-12, which is
also important for TH1-type and cytotoxic responses. In HIV patient blood, both
DC population numbers decrease as early as the primary stage.
[Back to top] NK Cells and HIV Infection: Lessons from
other Viruses
D.S.
Algara and P. Paul
Although the means
by which NK cells may contribute to anti viral defense are still incompletely
understood, various studies merge to a better comprehension of pathways that
mediate NK cell activation (NK cell mediated cytotoxic activity and cytokine
production) and their implications during the immune response towards a variety
of viruses. Characterization of a specific expression pattern of ligands for NK
receptors on virally infected cells and consequent modulation of NK cell
activity have provided new insights in the field. A major break through to a
direct evidence of a role for NK cells and NK cell receptors in immune
protection against viral infection, was the recent implication of the murine
activating Ly49H receptors in immune protection against MCMV infection.
Although much remains to be learned concerning implication of NK cells in HIV
infection, various reports have documented alteration in NK cell function and
numbers during the course of HIV infection or treatment of AIDS. This review
will focus on the current knowledge about the factors which might influence NK
cell activation
during various viral challenge and an emerging view of their alteration during
HIV infection.
[Back to top] Innate T-Cell Immunity in HIV Infections: The
Role of Vg9Vd2
T Lymphocytes
F.
Poccia, M.-L. Gougeon, C. Agrati, C. Montesano, F. Martini, C.D. Pauza, P.
Fisch, M. Wallace and M. Malkovsky
There is growing
interest in the use of innate immune reactions in the therapy and prophylaxis
of various diseases. Natural T (NT) lymphocytes that recognize infected cells
or microbial compounds without the classical genetic restriction by polymorphic
MHC molecules are crucial components of innate immunity. NT cells bearing the
Vγ9Vδ2 T-cell receptor (TCR) are broadly reactive against intracellular
pathogens, can lyse human immunodeficiency virus (HIV) infected cells, and
release cytokines capable of regulating HIV replication. The potent antiviral
activities of Vγ9Vδ2 T cells may help to contain viral spread during acute HIV
infection and/or to prevent the establishment of viral persistence. Substantial
changes in the composition and function of circulating γδ T-cell pools occur in
HIV-infected patients. These changes a) may contribute to the etiopathogenesis
of opportunistic infections and neoplasms, and b) are partly reversed by highly
active anti-retroviral therapy (HAART). In addition to direct antiviral
activities, activated γδ T cells influence dendritic cell maturation and the
adaptive αβ T-cell response. Vγ9Vδ2 T cells can be stimulated in vivo and in
vitro by various nonpeptidic antigens (NpAgs) and recent animal experimental
data suggest that activated Vγ9Vδ2 T cells may help to control SIV replication.
Currently, NpAgs are being assessed as potential therapeutic agents in AIDS,
tuberculosis and certain cancers susceptible to Vγ9Vδ2 T-cell effector
mechanisms.