Introduction
HBV is a hepatotropic, non cytopathic DNA virus, which can cause acute and chronic infection, and play an important role in the development of hepatocellular carcinoma- a leading cause of cancer mediated mortality worldwide.
In my paper I review some studies of how the virus can pass the immune system and persist. Then I discuss the mechanism by which it causes hepatocellular carcinoma. And all this show the importance of developing a powerful antiviral treatment.
Discussion
In chronic infection the viral persistence is associated with weakness in the immune system. It was suggested that an impaired function of Dentritic cells (DCs), the professional antigen presenting cells, account for the T and B cells hyporesponsiveness.
So studies have been done toward DCs in chronic HBV patients to understand the reduction of expression of co-stimulatory molecules and the impairment in cytokine secretion. Some suggested viral replication in DCs impairs its function. However these views were challenged by recent studies in vitro, which revealed that alloreactive and antigen specific T cell stimulatory capacities of DCs from chronic HBV infection were intact. And in DC population, both viral DNA and mRNA are undetectable by RT-PCR.
So other views appear and seem more reasonable. Some researchers indicate that the microenvironment changes in the liver and lymphocyte organs after HBV infection affect the maturation of DCs and leading to functional impairment in DCs and consequently impaired antigen presentation, leading to lower level of specific cell mediated immunity and cytotoxic T lymphocytes. This approach is so important for future immunotherapy.
However, there are some in vivo and vitro data indicate the interaction between the virus and DCs. Some studies demonstrate the presence of HBV DNA in blood DCs from patients with chronic HBV infection. Recent studies in vitro revealed that HBsAg is internalized by mDCs (myeloid DCs) in the blood, and so impairing the function of these mDCs.
More importantly, findings suggest that this impaired mDCs function improves upon viral load reduction. (1)
So it's now accepted that DCs play a big role in the recognition of HBV antigens and so the progress of HBV. DCs show TLRs and MR, the receptors for HBV antigens in DC that recognize the virus and regulate the immune response, including HBV clearance and resistance.
HBV infection play a a role in hepatocellular carcinoma (HCC). Several mechanisms by which HBV infection could lead to the development of HCC have been proposed. These mechanisms include insertional mutagenesis upon integration, trans-activation of the cellular genes, activation of signaling pathways, inactivation of tumor suppressor proteins, synergy with environmental carcinogenesis and host immune response.(2)
One of the open reading frames of HBV genome encoding a protein termed HBVx protein. This poliotropic function protein plays a major role in the pathogenesis of HCC.
The sequence of events in the development of HCC is still very poor, but a significant correlation has been made between long term carriage of the virus and developing HCC. Pathogenesis appears complex. This is because on the one hand, the HBV absence of reproducible in vitro HBV propagation system. On the other hand, the lack of evidence for HBV replication in tumor cells that arise in HBV infected patients.
"Recent studies have demonstrated that HBx possesses both cytoplasmic and nuclear activities. A number of cytoplasmic activities have been attributed to HBx including, the activation of Ras/Raf/mitogen-activated protein (MAP) kinase, MEKK1/Jun kinase, protein kinase C signal transduction pathways . Several putative nuclear targets of HBx have been revealed including, ATF-2/CREB transcriptional factors , RNA polymerase subunit RPB5, tumor suppressor protein p53 , TATA binding protein (TBP) , a putative DNA repair protein UV-DDB , TFIIH ,and RNA polymerase II . AP-2 and C/EBP have also been implicated as potential targets of HBx . HBx has been shown to stimulate transcription by RNA Polymerase II and III , Further, HBx was shown to induce either p53-mediated , or tumor necrosis factor alpha (TNFα)-mediated apoptotic destruction of liver cells." (2)
HBV infection treatment
Without any treatment the prognosis of HBV is very poor. The level of HBV-DNA is crucial determinant of progression to liver cirrhosis and HCC. Thus effective suppression of HBV-DNA is a major aim of treatment. This will be achieved by antiviral drugs, but challenged by the problem of developing resistant mutant viruses.(3)
INF-α is considered to be the traditional treatment. However the viral clearance rate is only 30%. Other nucleotide analogues have been used as viral replication inhibitors, but viral resistance remains. A new drug, Entecavir, has a good profile regarding both antiviral efficacy and resistance profile in the treatment of previously untreated patients. Enticavir is a step forward towards the treatment of chronic HBV.
From studies on the role of DCs in HBV infection, many other studies have been made to develop DC vaccine. They tried several methods, "such as culturing DCs with cytokines, pulsed with HBV antigens, and co-cultured with HBV DNA transgenic cells( antigen intake and internalization), and DC maturation to initiate adapted immunity". (1)
Some studies show a new method for clearing the virus fro chronic infection patients and played a critical role in the development of a strong therapeutic strategy for the treatment of chronic cases. That is based on the ability of TLR ligands to induce antiviral cytokines at the site of HBV replication. (1)
In HBV infection post liver transplantation the prophylaxis plays the major role by immune-globulin against HBV and nucleoside analogs. If prophylaxis failed , the treatment may be based on the resistance profile of the virus and previous antiviral exposure.(4)
In cases of co-infection with HCV ( which is approved by studies that it replicates in the same hepatocyte with HBV but without interference), studies show a possible way for management by the addition of a nucleoside/nucleotide analog for selective patients with HBV/HCV co-infection.(5)
Conclusion
There have been some methods to enhance efficient DC-based vaccine against HBV, but the interaction between DCs and HBV is still not clear, though. Some studies have also been made on the mechanism of carcinogenesis of the virus. These studies were made on HBVx protein and defined an inhibitory role of this protein in DNA excision repair mechanism.
