Productive infection of CD4+ and CD8+ mature human T cell populations and clones by human herpesvirus 6. Transcriptional down-regulation of CD3.
The susceptibility to infection by human herpes-virus 6 (HHV-6) of mature human T lymphocytes belonging to the two major subpopulations (i.e., CD3+ CD4+ CD8- and CD3+ CD4- CD8+) was investigated by using CD4+ or CD8+ T cell populations and clones derived from normal adult peripheral blood. Productive HHV-6 infection was observed in both CD4+ and CD8+ T cells. By days 2 to 6 after infection, increasing numbers of cells exhibited characteristic morphologic alterations, becoming enlarged, uniformly rounded and refractile as a consequence of the virus-induced cytopathic effect. During the course of HHV-6 infection, analysis of the surface membrane phenotype of the T cell populations and clones revealed a progressive decline in the expression of the CD3/TCR complex, whereas other T cell-associated markers (e.g., CD2) were unaffected. Northern blot analysis of mRNA extracted from HHV-6-infected T cells demonstrated a dramatic loss of the specific messages for the gamma-, delta-, and epsilon-chains of CD3. Infection by HHV-6, but not by HSV-1 or human CMV, elicited CD3/TCR down-regulation also in the neoplastic T cell line Jurkat. The down-regulation of CD3/TCR was dependent upon live virus infection, because previous inactivation of HHV-6 by heat (56 degrees C for 1 h) or UV light (16 J/m2) totally abrogated the effect. Expression of the immediate early or early genes of HHV-6 was not sufficient to induce CD3/TCR modulation, as indicated by studies with the viral DNA polymerase inhibitor phosphonoformic acid. The observation that both major subsets of mature TCR-alpha beta+ T lymphocytes are susceptible to HHV-6 infection indicates that this virus may have a broad spectrum of activity on the immune system. The transcriptional down-regulation of the CD3/TCR complex, by affecting a critical T cell recognition function, could be relevant to HHV-6 pathogenesis.
Laboratory of Tumor Cell Biology, National Cancer Institute, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892.
P
P
Lusso
M
M
Malnati
A
A
De Maria
C
C
Balotta
S E
SE
DeRocco
P D
PD
Markham
R C
RC
Gallo
D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis / Q000235:genetics*; D015152:Blotting, Northern; D017252:CD3 Complex; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology / Q000502:physiology; D016827:CD8 Antigens; D003588:Cytopathogenic Effect, Viral; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005814:Genes, Viral; D006566:Herpesviridae Infections / Q000235:genetics / Q000276:immunology*; D015654:Herpesvirus 6, Human / Q000235:genetics / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D012333:RNA, Messenger / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000382:microbiology* / Q000502:physiology; D014158:Transcription, Genetic; D015678:Viral Structural Proteins / Q000235:genetics
D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D016827:CD8 Antigens; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; D015678:Viral Structural Proteins