Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo.
Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of human immunodeficiency virus disease. However, the lack of suitable experimental models has hampered the elucidation of the mechanisms of HHV-6-mediated immune suppression. Here, we used ex vivo lymphoid tissue to investigate the cellular tropism and pathogenic mechanisms of HHV-6. Viral strains belonging to both HHV-6 subgroups (A and B) were able to productively infect human tonsil tissue fragments in the absence of exogenous stimulation. The majority of viral antigen-expressing cells were CD4(+) T lymphocytes expressing a nonnaive phenotype, while CD8(+) T cells were efficiently infected only with HHV-6A. Accordingly, HHV-6A infection resulted in the depletion of both CD4(+) and CD8(+) T cells, whereas in HHV-6B-infected tissue CD4(+) T cells were predominantly depleted. The expression of different cellular antigens was dramatically altered in HHV-6-infected tissues: whereas CD4 was upregulated, both CD46, which serves as a cellular receptor for HHV-6, and CD3 were downmodulated. However, CD3 downmodulation was restricted to infected cells, while the loss of CD46 expression was generalized. Moreover, HHV-6 infection markedly enhanced the production of the CC chemokine RANTES, whereas other cytokines and chemokines were only marginally affected. These results provide the first evidence, in a physiologically relevant study model, that HHV-6 can severely affect the physiology of secondary lymphoid organs through direct infection of T lymphocytes and modulation of key membrane receptors and chemokines.
Grivel
Jean-Charles
JC
Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Santoro
Fabio
F
Chen
Silvia
S
Fagá
Giovanni
G
Malnati
Mauro S
MS
Ito
Yoshinori
Y
Margolis
Leonid
L
Lusso
Paolo
P
D015703:Antigens, CD / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D046508:Culture Techniques; D015536:Down-Regulation; D005434:Flow Cytometry; D015654:Herpesvirus 6, Human / Q000472:pathogenicity*; D006801:Humans; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000378:metabolism; D014066:Palatine Tonsil / Q000503:physiopathology / Q000821:virology*; D019349:Roseolovirus Infections / Q000503:physiopathology* / Q000821:virology; D015854:Up-Regulation; D014779:Virus Replication
D015703:Antigens, CD; D017252:CD3 Complex; C497857:CD46 protein, human; D018946:Chemokine CCL5; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins