Alpha interferon inhibits human herpesvirus 8 (HHV-8) reactivation in primary effusion lymphoma cells and reduces HHV-8 load in cultured peripheral blood mononuclear cells.
Infection by human herpesvirus 8 (HHV-8) is associated with the development of Kaposi's sarcoma (KS). Since regression of KS can be achieved by treatment of the patients with alpha interferon (IFN-alpha), we analyzed the effects of IFN-alpha or anti-IFN-alpha antibodies (Ab) on HHV-8 latently infected primary effusion lymphoma-derived cell lines (BCBL-1 and BC-1) and on peripheral blood mononuclear cells (PBMC) from patients with all forms of KS and from at-risk subjects. IFN-alpha inhibited in a dose-dependent manner the amplification of HHV-8 DNA in BCBL-1 cells induced to lytic infection with tetradecanoyl phorbol acetate (TPA). This effect was associated with the inhibition of the expression of HHV-8 nut-1 and kaposin genes that are induced early and several hours, respectively, after TPA treatment. In addition, IFN-alpha inhibited virus production and/or release from BCBL-1 cells. Inhibition of nut-1 and kaposin genes by IFN-alpha was also observed in BC-1 cells induced with n-butyrate. Conversely, the addition of anti-IFN-alpha Ab to TPA-induced BCBL-1 cells resulted in a larger number of mature enveloped particles and in a more extensive cytopathic effect due to the neutralization of the endogenous IFN produced by these cells. IFN was also produced by cultured PBMC from HHV-8-infected individuals, and this was associated with a loss of viral DNA during culture. However, the addition of anti-IFN-alpha Ab or anti-type I IFN receptor Ab promoted the maintenance of HHV-8 DNA in these cells that was associated with the detection of the latency-associated kaposin RNA. Finally, the addition of IFN-alpha reduced the HHV-8 load in PBMC. Thus, IFN-alpha appears to have inhibitory effects on HHV-8 persistent infection of PBMC. These results suggest that, in addition to inhibiting the expression of angiogenic factors that are key to KS development, IFN-alpha may induce KS regression by reducing the HHV-8 load and/or inhibiting virus reactivation.
Monini
P
P
Laboratory of Virology, Institute of Virology, University "La Sapienza".
Carlini
F
F
Stürzl
M
M
Rimessi
P
P
Superti
F
F
Franco
M
M
Melucci-Vigo
G
G
Cafaro
A
A
Goletti
D
D
Sgadari
C
C
Butto'
S
S
Leone
P
P
Chiozzini
C
C
Barresi
C
C
Tinari
A
A
Bonaccorsi
A
A
Capobianchi
M R
MR
Giuliani
M
M
di Carlo
A
A
Andreoni
M
M
Rezza
G
G
Ensoli
B
B
D005814:Genes, Viral; D019288:Herpesvirus 8, Human / Q000254:growth & development / Q000276:immunology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000276:immunology* / Q000494:pharmacology; D007963:Leukocytes, Mononuclear / Q000821:virology; D008223:Lymphoma; D008297:Male; D009024:Morphogenesis; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D019562:Viral Load; D014771:Virion; D014775:Virus Activation
D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013755:Tetradecanoylphorbol Acetate