Hypoxia induces lytic replication of Kaposi sarcoma-associated herpesvirus.
There is substantial evidence that Kaposi sarcoma-associated herpesvirus (KSHV) plays an important role in the pathogenesis of all forms of Kaposi sarcoma (KS). It has been noted that KS commonly occurs in locations, such as the feet, where tissue may be poorly oxygenated. On the basis of this observation, the potential role of hypoxia in the reactivation of KSHV replication was explored by studying 2 KSHV-infected primary effusion lymphoma B-cell lines (BC-3 and BCBL-1) latently infected with KSHV. Acute and chronic exposure of these cells to hypoxia (1% O(2)) induced KSHV lytic replication, as indicated by an increase in intracellular lytic protein expression and detection of virus in cell supernatants by Western immunoblotting. In addition, hypoxia increased the levels of secreted viral interleukin-6. Moreover, hypoxia enhanced the lytic replication initiated by the viral inducer 12-O-tetradecanoylphorbol-13-acetate. Desferoxamine and cobalt chloride, 2 compounds that increase the intracellular levels of hypoxia-inducible factor 1, were also able to induce KSHV lytic replication. These studies suggest that hypoxia is an inducer of KSHV replication. This process may play an important role in the pathogenesis of KS.
Davis
D A
DA
HIV and AIDS Malignancy Branch, the Dermatology Branch, and the Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. dadavis@helix.nih.gov
Rinderknecht
A S
AS
Zoeteweij
J P
JP
Aoki
Y
Y
Read-Connole
E L
EL
Tosato
G
G
Blauvelt
A
A
Yarchoan
R
R
D001402:B-Lymphocytes / Q000821:virology; D015153:Blotting, Western; D002213:Capsid / Q000032:analysis; D015687:Cell Hypoxia; D002460:Cell Line; D003035:Cobalt / Q000494:pharmacology; D003676:Deferoxamine / Q000494:pharmacology; D006023:Glycoproteins / Q000032:analysis; D019288:Herpesvirus 8, Human / Q000302:isolation & purification / Q000502:physiology*; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000032:analysis; D014779:Virus Replication / Q000187:drug effects
D006023:Glycoproteins; D015850:Interleukin-6; C113454:K8.1 protein, Human herpesvirus 8; C110348:ORF59 protein, Human herpesvirus 8; D014764:Viral Proteins; D003035:Cobalt; C018021:cobaltous chloride; D003676:Deferoxamine; D013755:Tetradecanoylphorbol Acetate