Activation of Pattern Recognition Receptor-mediated Innate Immunity Inhibits the Replication of Hepatitis B Virus in Human Hepatocyte-derived Cells

November 6, 2008

J Virol. 2008 Oct 29. [Epub ahead of print]

Activation of Pattern Recognition Receptor-mediated Innate Immunity Inhibits the

Replication of Hepatitis B Virus in Human Hepatocyte-derived Cells.

Guo H, Jiang D, Ma D, Chang J, Dougherty AM, Cuconati A, Block TM, Guo JT.

Drexel Institute for Biotechnology and Virology Research, Department of

Microbiology and Immunology, Drexel University College of Medicine, Institute

for Hepatitis and Virus Research, Hepatitis B Foundation, Doylestown, PA 18901,

U.S.A.

Recognition of virus infections by pattern recognition receptors (PRRs), such as

Toll-like receptors (TLRs), retinoic acid-inducible gene I (RIG-I) and melanoma

differentiation associated gene 5 (MDA5), activates signaling pathways leading

to the induction of inflammatory cytokines that limit viral replication. To

determine the effects of PRR-mediated innate immune response on HBV replication,

a 1.3mer HBV genome was cotransfected into HepG2 or Huh7 cells with plasmid

expressing TLR adaptors, myeloid differentiation primary response gene 88

(MyD88) and TIR-domain-containing adaptor-inducing interferon-beta (TRIF), or

RIG-I/MDA5 adaptor, interferon promoter stimulator 1 (IPS-1). The results showed

that expressing each of the three adaptors dramatically reduced the levels of

HBV mRNA and DNA in both HepG2 and Huh7 cells. However, HBV replication was not

significantly affected by treatment of HBV genome-transfected cells with culture

media harvested from cells transfected with each of the three adaptors,

indicating that the adaptors-induced antiviral response was predominantly

mediated by intracellular factors, rather than secreted cytokines. Analyses of

involved signaling pathways revealed that activation of NFkappaB is required for

all three adaptors to elicit antiviral response in both HepG2 and Huh7 cells.

However, activation of IRF3 is only essential for induction of antiviral

response by IPS-1 in Huh7 cells, but not in HepG2 cells. Furthermore, our

results suggest that besides NFkappaB, additional signaling pathaway(s) are

required for TRIF to induce a maximum antiviral response against HBV. Knowing

the molecular mechanisms by which PRR-mediated innate defense responses control

HBV infections could potentially lead to the development of novel therapeutics

that evoke the host cellular innate antiviral response to control HBV

infections.

PMID: 18971270 [PubMed - as supplied by publisher]

November 6, 2008