HCV is accessible to antibodies. Plenty of peer-reviewed studies have reported presence of anti-HCV antibodies in both animal HCV infection models and natural human HCV infection. Thus, regardless of HCV’s association with the body’s low-density lipoprotein (LDL), an approach it uses to hijack host factors for its own replication, this doesn’t preclude its recognition and binding by antibodies.
In order to survive and replicate, HCV has to bind, enter, uncoat and then replicate within hepatocytes. To enter, HCV binds to hepatocyte-specific receptors, which include LDL receptor, CD81, scavenger receptor B type I (SR-BI), Claudin, (CLDN), Ocludin I (OCLN), and Niemann-Pick C1-like 1 cholesterol absorption receptor (NPC1L1). So the connection between LDL and HCV is that HCV’s evolved to piggy-back its way into hepatocytes by binding to hepatocyte cell-surface receptors for physiological metabolic products like LDL.
‘Does that mean HCV can never be neutralized by antibodies?‘
- No since many studies have shown HCV can be neutralized by antibodies.
- Let’s start with how soon HCV-specific antibodies appear following infection. In a prospective study of 12 young, injection drug users tested for circulating anti-HCV antibodies before, during and after HCV infection, HCV-specific antibodies were detected 8 to 20 weeks post-infection (1).
- A fraction of HCV-specific antibodies are neutralizing (nAbs), i.e., studies show they can inhibit HCV binding, entry and/or uncoating in in vitro culture systems (2,3).
- Both chronically infected and spontaneously clearing patients have such HCV-specific nAbs capable of inhibiting virus binding and entry (4, 5, 6, 7).
- Later the neutralizing HCV-specific antibody response, more likely infection will become chronic instead of being cleared (8, 9).
- OTOH, earlier and more cross-reactive HCV-specific nAbs, capable of neutralizing a broad range of HCV variants, higher the chance of spontaneous viral clearance (2, 3, 9, 10).
- HCV-specific nAb titers and their range increase over time (2, 8) though broader nAbs that appear later might be qualitatively different since they appear in the context of chronic infection, i.e., products of a plausibly ineffective immune response trying to catch up against an infection that’s effectively evading it (11).
- Qualitative difference between immune responses of spontaneously clearing and chronic HCV infections is further bolstered by the fact that HIV-coinfected chronic HCV patients have poor anti-HCV T cell responses (12, 13).
- T cell help is critical for B cell antibodies. Poorer the T cell help, less effective the B cell antibody response.
- Recently, several in vitro culture systems have been developed to analyze HCV-specific nAbs. These culture systems enable in vitro HCV replication (14, 15).
Logical question follows, namely, what part of HCV do HCV-specific nAbs target?
- Broad HCV-specific nAbs, i.e., those capable of neutralizing a broad range of HCV variants, tend to target epitopes derived from the envelope protein E2.
- Such nAbs establish contact with such epitopes at two discontinuous regions that span amino acid positions 424 to 443 (epitope II) and 529 to 535 (epitope III) (16).
- These two discontinuous regions overlap extensively with CD81 binding domains.
- Not surprising since CD81 is one of the main entry receptors used by HCV (17, 18).
- In particular, region 529 to 535 is extremely conserved with no escape mutants described thus far.
- OTOH, region 424 to 443 is more variable with several escape mutations that result in variants that nAbs target less efficiently (4).
Drawbacks of HCV-specific nAb studies
- Most studies use a limited panel of HCVpp (HCV pseudo particles).
- HCVpp are lab-created tools used as virus surrogates. To create HCVpp, human embryo kidney cells called 293T are transfected with 3 vectors. One encodes retroviral Gag and Pol proteins, 2nd for a reporter protein such as Luciferase or GFP (green fluorescent protein), and the 3rd for HCV glycoproteins E1 and E2. E1 and E2 are necessary for viral tropism and fusion (15).
- HCVpp are tools being used widely to figure out how HCV fuses to cell membrane and which inhibitors could block HCV entry.
- However, HCVpp clearly have critical limitations. For e.g., in 2012, NPC1L1 was identified as a new HCV entry factor (19). The native HCV requires this receptor to enter hepatocytes but HCVpp don’t. In other words, HCVpp don’t recapitulate all the critical and essential features of native HCV infection.
- Many studies tend to generalize capacity of HCV-specific Abs to neutralize by extrapolating results from their capacity to neutralize the HCV prototype strain, H77.
- Problem is the prototype H77 HCV strain is more sensitive to neutralization compared to other HCV strain variants (20).
- Netski, Dale M., et al. “Humoral immune response in acute hepatitis C virus infection.” Clinical infectious diseases 41.5 (2005): 667-675.
- Osburn, William O., et al. “Clearance of hepatitis C infection is associated with the early appearance of broad neutralizing antibody responses.” Hepatology 59.6 (2014): 2140-2151.
- Edwards, Victoria C., et al. “The role of neutralizing antibodies in hepatitis C virus infection.” Journal of General Virology 93.1 (2012): 1-19.
- Keck, Zhen-Yong, et al. “Mapping a region of hepatitis C virus E2 that is responsible for escape from neutralizing antibodies and a core CD81-binding region that does not tolerate neutralization escape mutations.” Journal of virology 85.20 (2011): 10451-10463.
- Lambers, Femke AE, et al. “Alarming incidence of hepatitis C virus re-infection after treatment of sexually acquired acute hepatitis C virus infection in HIV-infected MSM.” Aids 25.17 (2011): F21-F27.
- Grady, Bart P., et al. “Hepatitis C virus reinfection following treatment among people who use drugs.” Clinical infectious diseases 57.suppl 2 (2013): S105-S110.
- Pestka, Jan M., et al. “Rapid induction of virus-neutralizing antibodies and viral clearance in a single-source outbreak of hepatitis C.” Proceedings of the National Academy of Sciences 104.14 (2007): 6025-6030.
- Logvinoff, Carine, et al. “Neutralizing antibody response during acute and chronic hepatitis C virus infection.” Proceedings of the National Academy of Sciences of the United States of America 101.27 (2004): 10149-10154.
- Law, Mansun, et al. “Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge.” Nature medicine 14.1 (2008): 25-27.
- Osburn, William O., et al. “Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection.” Gastroenterology 138.1 (2010): 315-324.
- Von Hahn, Thomas, et al. “Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo.” Gastroenterology 132.2 (2007): 667-678.
- Kim, Arthur Y., et al. “The magnitude and breadth of hepatitis C virus–specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1.” Blood 105.3 (2005): 1170-1178.
- Harcourt, G., et al. “Diminished frequency of hepatitis C virus specific interferon γ secreting CD4+ T cells in human immunodeficiency virus/hepatitis C virus coinfected patients.” Gut 55.10 (2006): 1484-1487.
- Lindenbach, Brett D., et al. “Complete replication of hepatitis C virus in cell culture.” Science 309.5734 (2005): 623-626.
- Ashfaq, Usman Ali, et al. “In-vitro model systems to study Hepatitis C Virus.” Genet Vaccines Ther 9.7 (2011).
- Keck, Zhen-Yong, et al. “Hepatitis C virus E2 has three immunogenic domains containing conformational epitopes with distinct properties and biological functions.” Journal of virology 78.17 (2004): 9224-9232.
- Pileri, Piero, et al. “Binding of hepatitis C virus to CD81.” Science 282.5390 (1998): 938-941.
- Drummer, Heidi E., Kirilee A. Wilson, and Pantelis Poumbourios. “Identification of the hepatitis C virus E2 glycoprotein binding site on the large extracellular loop of CD81.” Journal of virology 76.21 (2002): 11143-11147.
- Sainz Jr, Bruno, et al. “Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor.” Nature medicine 18.2 (2012): 281-285.
- Tarr, Alexander W., et al. “Hepatitis C patient-derived glycoproteins exhibit marked differences in susceptibility to serum neutralizing antibodies: genetic subtype defines antigenic but not neutralization serotype.” Journal of virology 85.9 (2011): 4246-4257.