Hepatitis B virus binds to peripheral blood mononuclear cells via the pre S1 protein

doi:10.1016/0168-8278(91)90939-9

Journal of Hepatology

Volume 12, Issue 2, March 1991, Pages 203-206

https://doi.org/10.1016/0168-8278(91)90939-9 Get rights and content

Abstract

The hepatitis B virus has been documented in hepatic and extrahepatic compartments, including bone marrow and peripheral blood cells. The viral protein involved in the attachment to human hepatocytes has been identified within the N-terminus of the pre S1 envelope protein. Using recombinant particles containing the pre S1, pre S2 and S encoded sequences, we studied which virus envelope protein is involved in binding to peripheral blood cells. Mononuclear cells of 20 healthy subjects bound ¹²⁵I-labelled particles, with a S/N ratio higher than 2.5 (range 2.69–7.77). Binding was abolished by trypsinization. B lymphocytes and monocytes were found to bind viral particles much more efficiently compared to T cells and granulocytes. A monoclonal antibody (MA 18/7), recognizing the (27–49) pre S1 sequence, completely inhibited viral particle attachment to PBMC, while anti-pre S2 (Q 19/10) and anti-S (20/2) monoclonal antibodies had no effect. We conclude that the pre S1 sequence is involved in HBV attachment to PBMC and to hepatocytes. The nature of the cellular attachment site is unknown, but it might be a receptor for physiologic ligands, as occurs with other viruses.

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Cited by (32)

Hepatitis B virus antigens impair NK cell function
2016, International Immunopharmacology
Citation Excerpt :
A number of potential host cell–expressed HBV receptor candidates for allowing HBV entry into host cells have been described in the last three decades, such as polymerized human serum albumin (pHSA), asialoglycoprotein receptor (ASGPR), human apolipoprotein H (ApoH), and Annexin V, but only NTCP (sodium taurocholate cotransporting polypeptide) was generally recognized as the receptor mediated cellular entry of HBV so far [33,34]. Additionally, a previous study demonstrated HBV-encoded pre-S1 sequence was involved in HBV attachment to PBMCs, but the exact mechanisms of attachment and entrance into differentiated host cells by this system remained unclear [35]. Whether HBV antigens can attachment to NK cells and interact with NK cells is worth considering.
An inadequate immune response of the host is thought to be a critical factor causing chronic hepatitis B virus (CHB) infection. Natural killer (NK) cells, as one of the key players in the eradication and control of viral infections, were functionally impaired in CHB patients, which might contribute to viral persistence. Here, we reported that HBV antigens HBsAg and HBeAg directly inhibited NK cell function. HBsAg and/or HBeAg blocked NK cell activation, cytokine production and cytotoxic granule release in human NK cell-line NK-92 cells, which might be related to the downregulation of activating receptors and upregulation of inhibitory receptor. Furthermore, the underlying mechanisms likely involved the suppression of STAT1, NF-κB and p38 MAPK pathways. These findings implicated that HBV antigen–mediated inhibition of NK cells might be an efficient strategy for HBV evasion, targeting the early antiviral responses mediated by NK cells and resulting in the establishment of chronic virus infection. Therefore, this study revealed the relationship between viral antigens and human immune function, especially a potential important interaction between HBV and innate immune responses.
Molecular Biology of the Hepatitis B Virus for Clinicians
2012, Journal of Clinical and Experimental Hepatology
Citation Excerpt :
This tissue specificity is thought to be due to one or more poorly characterized hepatocyte-specific HBV receptors and/or co-receptors. Pseudotyping experiments and other studies indicate that the preS1 protein (specifically, amino acids 21–47) participates in cellular receptor binding.25–27 A variety of human cellular proteins have been shown to bind HBV envelope glycoproteins.
Hepatitis B virus (HBV) infection is one of the major global health problems, especially in economically under-developed or developing countries. HBV infection can lead to a number of clinical outcomes including chronic infection, cirrhosis and liver cancer. It ranks among the top 10 causes of death, being responsible for around 1 million deaths every year. Despite the availability of a highly efficient vaccine and potent antiviral agents, HBV infection still remains a significant clinical problem, particularly in those high endemicity areas where vaccination of large populations has not been possible due to economic reasons.
Although HBV is among the smallest viruses in terms of virion and genome size, it has numerous unique features that make it completely distinct from other DNA viruses. It has a partially double stranded DNA with highly complex genome organization, life cycle and natural history. Remarkably distinct from other DNA viruses, it uses an RNA intermediate called pregenomic RNA (pgRNA) and reverse transcriptase for its genome replication. Genome replication is accomplished by a complex mechanism of primer shifting facilitated by direct repeat sequences encoded in the genome. Further, the genome has evolved in such a manner that every single nucleotide of the genome is used for either coding viral proteins or used as regulatory regions or both. Moreover, it utilizes internal in-frame translation initiation codons, as well as different reading frames from the same RNA to generate different proteins with diverse functions. HBV also shows considerable genetic variability which has been related with clinical outcomes, replication potential, therapeutic response etc. This review aims at reviewing fundamental events of the viral life cycle including viral replication, transcription and translation, from the molecular standpoint, as well as, highlights the clinical relevance of genetic variability of HBV.
Chronic hepatitis B, non-Hodgkin's lymphoma, and effect of prophylactic antiviral therapy
2011, Journal of Clinical Virology
Citation Excerpt :
In contrast to the association between hepatitis C virus (HCV) and NHL, studies of the mechanism linking HBV to NHL induction have been limited. HBV can bind to peripheral blood mononuclear cells (PBMCs) via the pre S1 protein, and B lymphocytes and monocytes were found to bind viral particles more efficiently, compared with T cells.20 HBV DNA integration in PBMCs, as well as hepatocytes, was demonstrated in HBV carriers and anti-HBc only positive individuals, which was confirmed in animal models.21,22
Hepatitis B virus (HBV) infection can be associated with non-Hodgkin's lymphoma (NHL), and prophylactic antiviral therapy is recommended for NHL patients with chronic HBV infection who are receiving anticancer chemotherapy.
The aims of this study were to investigate the association between HBV infection and NHL, and to evaluate the application rate and the effect of prophylactic antiviral therapy for HBV-infected NHL patients.
A retrospective, case–control study was performed.
The prevalence of hepatitis B surface antigen in 344 patients who were consecutively diagnosed with NHL from May 2003 to October 2009 (44 of 344; 12.8%) was significantly higher than that of 688 age- and sex-matched health-check examinees (24 of 688; 3.5%) (adjusted odds ratio, 4.08; 95% confidence interval, 2.44–6.85). T cell type NHL, as well as B cell type, showed a significant association with HBV carrier rate. Among 32 NHL patients who received anticancer chemotherapy, 30 patients (93.8%) received prophylactic antiviral therapy, primarily lamivudine. However, HBV DNA monitoring during antiviral therapy was frequently omitted in hemato-oncology clinics. While there was no occurrence of hepatitis flare during antiviral therapy, withdrawal hepatitis after discontinuation of antiviral drug occurred frequently (60%).
HBV may play a significant role in development of NHL, which prompts further study on the lymphomagenic mechanism of HBV infection. Prophylactic antiviral therapy was administered during chemotherapy to almost all of the NHL patients with HBV infection; however, further investigation should be conducted for determination of optimal duration and monitoring of antiviral therapy.
Biological and clinical implications of HBV infection in peripheral blood mononuclear cells
2008, Autoimmunity Reviews
Citation Excerpt :
It was demonstrated that recombinant particles containing the S gene products or the preS2 and S derived protein did not bind peripheral blood mononuclear cells. Only recombinant particles carrying the preS1, preS2 and S encoded proteins were able to bind [34]. These results recall the findings observed in the liver, where the preS1 encoded protein of the surface antigen has been identified as the major binding site responsible for the attachment of the virus to liver cell surface [35].
The liver is the main site of HBV replication, however extrahepatic organs, such as the lymphoid system, are an important reservoir of the virus. Viral DNA into different mononuclear cell subsets has been mainly detected in monocytes and B lymphocytes. The attachment site of the virus has been identified in the preS1 encoded protein of the virus envelope, the same involved in hepatocyte infection. The risk of HBV transmission by infected lymphocytes has been clearly documented in the setting of liver transplantation where de novo HBV infection has been found in up to about 80% of liver grafts from HBsAg negative but anti-HBc positive donors. In the hemodialysis setting the percentage of HBV DNA detection in mononuclear cells of HBsAg negative patients has been described in up to 54% of the cases. Vertical transmission studies indicate that HBV-infected mononuclear cells of the mother may result in viral infection of mononuclear cells of the newborns and possible HBV vaccine response failure. HBV can also infect bone marrow cells and in vitro studies demonstrate a block of hematopoiesis by HBV, supporting clinical observations of isolate cases of aplastic anemia associated to the infection.
Detection of cellular receptors specific for the hepatitis B virus preS surface protein on cell lines of extrahepatic origin
2000, Biochemical and Biophysical Research Communications
Hepatitis B virus infection is primarily mediated by the interaction of the preS region of the viral envelope protein with its still unknown cellular receptor. Using recombinantly expressed preS proteins, the distribution of preS-binding receptors on cell lines from extrahepatic origins was determined by immunofluorescence and flow cytometry. In contrast to human liver cell lines, most cell lines from extrahepatic origins did not bind preS proteins. Nevertheless, exceptions were found in the bone marrow-derived cell line, KG-1, and the osteogenic sarcoma cell line SaOS-2, as well as in the previously reported EBV-transformed B-cell line, Wa. To determine the biochemical nature of these receptors, Wa-cells were cell surface biotinylated and the preS-binding receptors were isolated by immunoprecipitation. A specific band with a molecular weight of ∼30 kDa was identified in a SDS-polyacrylamide gel, which further characterization is expected to provide clues regarding the infection mechanism of HBV in hepatic- and extra-hepatic cells.
Human interleukin-6 facilitates hepatitis B virus infection in vitro and in vivo
2000, Virology
Background and aim. Research on hepatitis B virus (HBV) infection in vivo has been limited due to the absence of a suitable animal model. We have developed a human–mouse radiation chimera in which normal mice, preconditioned by lethal total body irradiation and radioprotected with SCID mouse bone marrow cells, are permissive for engraftment of human hematopoietic cells and solid tissues. This resulting human–mouse model, which comprises three genetically disparate sources of tissue, is therefore termed Trimera. This study was aimed at assessing the effect of human IL-6 on HBV infection in vivo in Trimera mice. Methods. Trimera mice were transplanted with human liver tissue fragments or with HepG2-derived cell lines, which had been previously infected ex vivo with HBV in the presence or absence of human interleukin-6 (hIL-6) and in the presence of anti-IL-6-neutralizing antibodies. Results. HBV sequences appeared in the sera of animals in which the liver tissue was incubated with both HBV and hIL-6 prior to transplantation. A similar result was obtained when a human hepatoblastoma cell line (HepG2), expressing the hIL-6 receptor, was infected ex vivo with HBV in the presence of hIL-6 prior to their injection into spleens of Trimera mice. However, when liver fragments were infected ex vivo and simultaneously treated with neutralizing antibodies against hIL-6 or were incubated with HBV prior to transplantation without hIL-6, the rate of mice positive for HBV DNA in their sera was lower. Human mononuclear cells are also permissive for HBV infection in vitro: in the presence of hIL-6 the infection of these cells is enhanced; and this infection is suppressed by the chimeric protein named Hyper-IL-6, generated by the fusion of hIL-6 to the soluble hIL-6 receptor (sIL-6Rα, gp80). Conclusion. hIL-6 facilitates HBV infection in vitro and in vivo.

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Regular paperHepatitis B virus binds to peripheral blood mononuclear cells via the pre S1 protein

Abstract

J Hepatol

Virology

Trends Physiol Sci

Gastroenterology

Human liver plasma membranes contain receptors for the hepatitis G virus pre S1 region and, via polymerized human serum albumin, for the pre S2 region

J Virol

A candidate vaccine for hepatitis B containing a complete viral surface protein

Hepatoogy

Regular paper
Hepatitis B virus binds to peripheral blood mononuclear cells via the pre S1 protein