Pathogenic effects of human herpesvirus 6 in human lymphoid tissue ex vivo.
http://www.ncbi.nlm.nih.gov/pubmed/12857897
Abstract
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.
