Regulation of CC chemokine receptor 5 in hepatitis G virus infection.
BACKGROUND
Epidemiological data demonstrate an association between hepatitis G virus (HGV) co-infection and improved survival of HIV-positive individuals. However, the mechanism by which HGV affects progression of HIV disease remains unclear. As down-regulation of CC chemokine receptor 5 (CCR5) delays HIV progression, we investigated whether CCR5 expression is altered by exposure of lymphocytes to HGV proteins.


METHODS
A cross-sectional analysis of CCR5 expression was carried out on CD4 and CD8 T lymphocytes of 11 HGV-positive and 12 HGV-negative persons, who were homozygous for the CCR5 wild-type gene. Binding of the HGV E2 protein to CD81 was analysed by flow cytometry. Lymphocytes were stimulated with immobilized HGV E2, anti-CD81 or serum proteins from HGV-infected subjects and changes in CCR5 expression and CC chemokine secretion were determined.


RESULTS
We demonstrate that the HGV envelope protein E2 specifically binds to CD81 on T lymphocytes. This interaction induces a dose-dependent release of RANTES and down-regulation of CCR5 surface expression with concomitant intra-cellular accumulation of CCR5 proteins. This effect of HGV E2 on CCR5 expression was confirmed when lymphocytes were incubated with serum proteins from HGV-infected subjects. Finally, our cross-sectional analysis revealed CCR5 expression to be reduced by 53% and 36% on CD4 and CD8 lymphocytes of HGV-infected subjects, respectively (P < 0.01).


CONCLUSIONS
Our results demonstrate that an interaction of HGV E2 with CD81 leads to increased RANTES secretion and decreased CCR5 surface expression. This mechanism might contribute to the delayed progression of HIV-infection in HGV-coinfected patients.
Nattermann
Jacob
J
Department of General Internal Medicine, Rheinische Friedrich-Wilhelms-Universität, Bonn, Germany.
Nischalke
Hans-Dieter
HD
Kupfer
Bernd
B
Rockstroh
Jürgen
J
Hess
Lothar
L
Sauerbruch
Tilman
T
Spengler
Ulrich
U
D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D054407:Chemokine CCL4; D018946:Chemokine CCL5 / Q000097:blood / Q000378:metabolism; D003430:Cross-Sectional Studies; D018178:Flaviviridae Infections / Q000276:immunology*; D005434:Flow Cytometry; D029407:GB virus C; D006525:Hepatitis, Viral, Human / Q000276:immunology*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D008565:Membrane Proteins / Q000378:metabolism; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000032:analysis* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins / Q000378:metabolism
D015703:Antigens, CD; C554798:CD81 protein, human; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; D019713:Receptors, CCR5; D060225:Tetraspanin 28; D014759:Viral Envelope Proteins; C107619:glycoprotein E2, GB virus C