Sex Hormones and HCV

An Unresolved Mystery

Radwa Y Mekky; Ahmed I Abdelaziz

Disclosures

Expert Rev Gastroenterol Hepatol. 2013;7(1):69-75. 

In This Article

Viral Behavior Among Different Genders

Although HCV infection is characterized by persistence, it is documented that 15–30% of individuals show spontaneous clearance of the virus.[17] Gender is one of the main factors that has been widely reported to influence the HCV clearance rate, where HCV-infected females have shown higher clearance rates when compared with their male counterparts.[3,4]

The disparity in self resolution of HCV infection among males and females suggests a role for sex hormones in influencing viral behavior. However, the impact of female sex hormones on HCV remains enigmatic; it is not known whether they hold a beneficial or detrimental role towards virological clearance. For example, 17β-estradiol was found to act directly on the virus itself by possessing an inhibitory effect on mature virion production in cultured Huh-7.5 cells transfected with viral replicon (Figure 1).[18] However, in the same study this inhibitory effect was not observed upon treatment with progesterone.[18] Moreover, the coumestans family of phytoestrogens, naturally occurring estrogen-like compounds derived from some plants and belonging to the flavonoids category of phytoestrogens, was reported as novel candidates for targeting viral replication by acting on HCV NS5B, a nonstructural viral protein essential for replication.[19] Pregnancy, a state of elevated estrogen and progesterone, was found to decrease the activity of chronic HCV. This effect was abolished after delivery.[20] In contrast to the aforementioned studies, Watashi et al. reported that estrogen receptor-α is functionally associated with HCV replication and its blockage with tamoxifen, a selective estrogen receptor modulator, may be a novel approach for targeting HCV infection (Figure 1).[21] The conflicting data concerning the influence of female sex hormones on HCV necessitate an in-depth look into their effects at various stages of the viral life cycle.

Figure 1.

Sex hormone impact on the HCV life cycle. 1. HCV enters the host cells through cell surface receptors CD81, SR-B and LDLR. Tight junction proteins OCLN and CLDN are co-receptor molecules important for viral entry. 2. After viral entry, uncoating of the virus and cytoplasmic release takes place. 3. Translation occurs on the rough endoplamic reticulum. 4. Association of produced viral proteins with the ER results in production of a membranous web upon which replication takes place. 5. Assembly of the viral proteins occurs. 6. Mature virions exit host cell via exocytosis. Testosterone was found to enhance HCV entry by positively (+) regulating both SR-B as well as CLDN. Oppositely, estrogen decreased (-) the expression of SR-B. Estrogen receptor a was found to be a crucial host factor used by the virus to promote its own replication. However, estrogen was reported to inhibit (-) the release of mature virions from infected Huh-7 cell lines.
CLDN: Claudin; ER: Endoplasmic reticulum; LDLR: Low-density lipoprotein receptors; OCLN: Occludin; SR-B: Scavenger receptors class B.

The impact of testosterone on HCV behavior represents another piece of the puzzle. Surprisingly, to date, the effect of testosterone on HCV replication has not been studied. However, it was reported that testosterone enhanced the expression of scavenger receptors, which are critical for viral entry, on both HepG2 cell lines and human monocyte-derived macrophages in a dose-dependent manner.[22,23] Interestingly, estrogen suppressed the expression of hepatic scavenger receptors (Figure 1).[24] In the same context, testosterone enhanced the expression of the tight junction protein claudin, which also plays a central role in HCV cellular entry (Figure 1).[25,26] These aforementioned studies might elucidate the role of testosterone in enhancing viral entry to host cells thus highlighting a gender bias toward HCV response.

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