European Journal of Medical Research - Deutsche AIDS ...

124 EUROPEAN JOURNAL OF MEDICAL RESEARCH
June 27, 2007
probably plays an important role in the pathological expression
of this chemokine.
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F.14 (Vortrag)
Suppressive HAART abrogates HIV-induced
intestinal barrier impairment and mucosal
immune activation
Epple H.-J. 1 , Schneider T. 1 , Tröger H. 1 , Kunkel D. 1 ,
Allers K. 1 , Moos V. 1 , Fromm M. 2 , Zeitz M. 1 ,
Schulzke J.-D. 1
1 Charité, Campus Benjamin Franklin, Med. Klin. I,
Gastroenterologie, Infektiologie, Rheumatologie, Berlin,
Germany, 2 Charité, Campus Benjamin Franklin, Institut für
Klinische Physiologie, Berlin, Germany
Objective: A barrier defect of the intestinal mucosa has been
suggested as central mechanism of the hyper immune activation
characteristic for chronic HIV infection. However, although
highly effective antiretroviral therapy (HAART) reduces
the general immune activation in HIV-infected patients,
the effect of HAART on the HIV-induced epithelial barrier
defect is unknown as are its underlying mechanisms. In this
study we investigated the effect of suppressive HAART on
the HIV-induced intestinal barrier defect and mucosal cytokine
secretion.
Methods: Epithelial barrier function was characterized in
duodenal biopsies obtained from 11 untreated, 8 suppressively
treated HIV-infected patients, and 9 HIV-seronegative controls
by impedance spectroscopy and 3H-mannitol fluxes. Villus/crypt
ratio was determined microscopically. Epithelial
apoptotic rate was analyzed by TUNEL staining. Expression
of tight junction proteins was quantified by densitometric
analysis of immunoblots. Mucosal cytokine production was
determined by cytometric bead array.
Results: Untreated but not treated HIV infection was associated
with a marked reduction of the epithelial resistance, an increase
of mannitol permeability and pronounced villus atrophy.
Accordingly, mucosal production of interleukin (IL)-2,
interferon-g, IL-4, IL-5, and tumor necrosis factor-a was increased
in untreated but not in treated HIV patients. Furthermore,
in treated patients epithelial apoptosis was increased,
the expression of the sealing tight junction protein claudin-1
was reduced and that of the pore-forming claudin-2 was increased.
Conclusions: The HIV-induced intestinal barrier defect and
villus atrophy are reversed by suppressive HAART. Accordingly,
suppressive HAART strongly reduces the mucosal production
of inflammatory cytokines which is highly increased
in untreated HIV-infected patients. Finally, we identified increased
epithelial apoptosis and an altered tight junction composition
as mechanisms of the HIV-induced barrier defect.
Our data indicate that interruption of the self-perpetuating cycle
of mucosal immune activation by suppressive HAART
leads to reconstitution of the epithelial barrier function and
may thus contribute to the reduction of systemic immune activation.
F.15 (Poster)
Pronounced increase of mucosal FoxP3+
regulatory CD4+ T cells early after the start of
ART in chronically SIV infected macaques
Allers K. 1 , Loddenkemper C. 2 , Epple H.-J. 1 ,
Stahl-Hennig C. 3 , Schrod A. 3 , Sauermann U. 3 ,
Verena M. 1 , Schneider T. 1
1 Medical Clinic I, Charité - Campus Benjamin Franklin,
Gastroenterology, Infectious Diseases and Rheumatology,
Berlin, Germany, 2 Medical Clinic I, Charité - Campus
Benjamin Franklin, Institute of Pathology, Berlin, Germany,
3 German Primate Centre, Department of Virology and
Immunology, Goettingen, Germany
HIV infection is associated with chronic immune activation
and progressive loss in the number and function of CD4+ T
cells. Antiretroviral therapy (ART) generally results in a reconstitution
of T cells. However, in a small fraction of patients
receiving ART a hyperinflammatory disorder occurs despite
decreased viral load and reconstitution of T cells. The
mechanisms responsible for this immune inflammatory reconstitution
syndrom (IRIS) are unknown.
Naturally occurring regulatory CD4+ T cells (Treg) constitutively
express CD25 and FoxP3 and have recently been described
as a subset of T cells with immunosuppressive properties.
Previously we found evidences for an important role of
mucosal Treg in untreated HIV infection and observed a return
of Treg numbers to normal levels after ART. However,
the dynamics of Treg normalization following ART are unknown.
In this study, we analyzed the peripheral and mucosal
lymphocyte subset distribution in the course of untreated and
treated SIVmac251 infection in six rhesus macaques by flow
cytometry. Quantifications were performed by immunohistochemistry
and BD TruCountTM. In addition, functional tests
were performed.
Peripheral Treg decreased during untreated SIV infection
and normalized after start of ART. In contrast, mucosal Treg
increased and reached highest levels early after initiation of
ART. We did not find significant correlations between Th1 or
Th2 cytokines in the gut mucosa and increasing Treg. Thus,
one regulatory function of Treg could consist in sustaining
levels of Th1 and Th2 cytokines that hold immune activation
and inflammation in a non-detrimental state. CD4+ T cell response
against SIV peptides was restricted to the acute phase
of infection and not restored after start of ART. Interestingly,
there was a highly significant inverse correlation between the
SIV specific response in the peripheral blood and the frequency
of mucosal Treg. Therefore, we suggest that Treg located
at lymphatic sites play an important role in suppressing immune
responses. Taken together, our results indicate that Treg
accumulate at sites of high immune activation to suppress
detrimental hyperactivation. We hypothesize that a loss of
Treg induces hyperinflammatory disorder resulting in IRIS in
patients receiving ART.