循环 Pre-S/S 准种是否会影响 HBV 感染 HBeAg 阴性期的乙肝表面抗原水平？
Do the circulating Pre-S/S quasispecies influence hepatitis B virus surface antigen levels in the HBeAg negative phase of HBV infection?
机构信息
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Pisa University Hospital, Pisa, Italy.
出版信息
Aliment Pharmacol Ther. 2020 Jun;51(12):1406-1416. doi: 10.1111/apt.15753. Epub 2020 May 11.
BACKGROUND
Virus, host factors and their interplay influence Hepatitis B surface Antigen serum levels during Hepatitis B Virus (HBV) infection course and treatment.
AIM
To study the Pre-S/S circulating quasispecies in a cohort of untreated, HBeAg negative, genotype-D, HBsAg carriers.
METHODS
We studied 260 carriers: 71 with HBeAg negative infection (ENI; HBV-DNA ≤2000 IU/mL); 42 Grey Zone (GZ; HBV-DNA ≤20 000 IU/mL); 82 chronic hepatitis (CH) and 65 cirrhosis (CI) (HBV-DNA > 20 000 IU/mL). Population sequencing was applied to identify Pre-S/S gene mutations responsible for any amino acid substitution or potential biological/antigenic implications (M-muts) on HBsAg.
RESULTS
HBsAg serum levels were lower in ENI + GZ than in CH + CI (2.61 [-1.10/4.06] vs 3.62 [2.41/4.92] log IU/mL, P < 0.001) and in CI than CH (3.48 [2.41/4.38] vs 3.66 [2.57/4.92] log IU/mL, P < 0.001). M-muts were found in 73 (28.1%) cases: 5 (7.0%) ENI, 3 (7.1%) GZ, 26 (31.7%) CH, 39 (60.0%) CI (P < 0.001) and mostly in Pre-S2 (17.6%) than Pre-S1 (5.8%) and Small-S (10.8%; P < 0.001). Overall HBsAg serum levels were higher in carriers with M-muts (3.56 [0.95/4.38] vs 3.17 [-1.10/4.92] log IU/mL, P < 0.001), but comparable in carriers with or without M-mut when considering separately ENI + GZ (2.84 [0.95/3.89] vs 2.61 [-1.10/4.06] log IU/mL, P = 0.330] and CH + CI (3.57 [2.67/4.38] vs 3.63 [2.41/4.92] log IU/mL, P = 0.37). Infection phase (β: 0.422, P < 0.001), age (β: -0.260, P < 0.001), ALT (β: -0.103, P = 0.045), liver stiffness (β: -0.118, P = 0.039) and HBV-DNA (β: 0.384, P < 0.001), but not M-mut were independently associated with HBsAg serum levels.
CONCLUSIONS
In HBeAg negative, genotype-D, carriers Pre-S/S heterogeneity increases with severity of liver disease, but does not influence HBsAg serum levels, that in low viraemic carriers are associated with an effective control of HBV.
背景
病毒、宿主因素及其相互作用影响乙型肝炎病毒（HBV）感染过程和治疗期间乙型肝炎表面抗原（HBsAg）血清水平。
目的
研究未经治疗的 HBeAg 阴性、基因型 D、HBsAg 携带者中 Pre-S/S 循环准种。
方法
我们研究了 260 名携带者：71 名 HBeAg 阴性感染（ENI；HBV-DNA ≤2000 IU/mL）；42 名灰色地带（GZ；HBV-DNA ≤20,000 IU/mL）；82 名慢性肝炎（CH）和 65 名肝硬化（CI）（HBV-DNA>20,000 IU/mL）。对人群进行序列分析，以确定导致 HBsAg 任何氨基酸取代或潜在生物学/抗原性影响（M-muts）的 Pre-S/S 基因突变。
结果
ENI+GZ 的 HBsAg 血清水平低于 CH+CI（2.61 [-1.10/4.06] 与 3.62 [2.41/4.92] log IU/mL，P<0.001）和 CI 低于 CH（3.48 [2.41/4.38] 与 3.66 [2.57/4.92] log IU/mL，P<0.001）。在 73 例（28.1%）中发现 M-muts：5 例（7.0%）ENI，3 例（7.1%）GZ，26 例（31.7%）CH，39 例（60.0%）CI（P<0.001），主要在 Pre-S2（17.6%）中，而不是 Pre-S1（5.8%）和 Small-S（10.8%；P<0.001）。总体而言，携带 M-muts 的 HBsAg 血清水平较高（3.56 [0.95/4.38] 与 3.17 [-1.10/4.92] log IU/mL，P<0.001），但在考虑 ENI+GZ 时，携带或不携带 M-mut 的携带者之间相似（2.84 [0.95/3.89] 与 2.61 [-1.10/4.06] log IU/mL，P=0.330）和 CH+CI（3.57 [2.67/4.38] 与 3.63 [2.41/4.92] log IU/mL，P=0.37）。感染阶段（β：0.422，P<0.001）、年龄（β：-0.260，P<0.001）、ALT（β：-0.103，P=0.045）、肝硬度（β：-0.118，P=0.039）和 HBV-DNA（β：0.384，P<0.001），但不是 M-mut 与 HBsAg 血清水平独立相关。
结论
在 HBeAg 阴性、基因型 D 的携带者中，Pre-S/S 异质性随着肝病的严重程度增加，但不影响 HBsAg 血清水平，在低病毒血症携带者中，HBsAg 血清水平与 HBV 的有效控制有关。
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