Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6.
During intrathymic T-cell ontogenesis, functionally competent CD3+CD4+CD8- and CD3+CD4-CD8+ T lymphocytes develop from immature CD4-CD8- thymocytes after transiently acquiring a double-positive CD4+CD8+ phenotype. The partition between CD4+CD8- and CD4-CD8+ T cells is generally considered to be irreversible, although a small percentage of circulating CD3+ T lymphocytes coexpressing CD4 and CD8 molecules has been identified. It has been suggested that in CD8+ T cells the CD4 genes may be methylated and thus highly repressed, whereas in CD4+ T cells the CD8 genes are unmethylated and their transcription can be induced by physiological stimuli such as interleukin-4. Here, we demonstrate that infection with human herpesvirus 6 (HHV-6), a virus proposed as a potential cofactor in AIDS, dramatically upregulates the expression of CD4--the receptor for human immunodeficiency virus type-1 (HIV-1)--in a human neoplastic T-cell line. More importantly, HHV-6 induces de novo expression of CD4 messenger RNA and protein in normal mature CD8+ T lymphocytes, rendering them susceptible to infection with HIV-1. These findings demonstrate that human CD3+CD4-CD8+ T lymphocytes can reacquire CD4 in the post-thymic life and elucidate a novel mechanism--receptor regulation--through which HHV-6 may positively interact with HIV-1 in coinfected patients.
Lusso
P
P
Laboratory of Tumor Cell Biology, National Cancer Institute, Bethesda, Maryland 20892.
De Maria
A
A
Malnati
M
M
Lori
F
F
DeRocco
S E
SE
Baseler
M
M
Gallo
R C
RC
D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001483:Base Sequence; D017252:CD3 Complex; D015704:CD4 Antigens / Q000378:metabolism*; D016827:CD8 Antigens; D002460:Cell Line; D015658:HIV Infections / Q000382:microbiology*; D006566:Herpesviridae Infections / Q000378:metabolism*; D015654:Herpesvirus 6, Human / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000737:chemistry; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000382:microbiology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D009841:Oligonucleotides; D011948:Receptors, Antigen, T-Cell