开发慢性乙型肝炎的治疗方法需要一种新的方法

StephenW

开发慢性乙型肝炎的治疗方法需要一种新的方法
药物开发的普遍教条是不够的；是时候重新围绕免疫系统开展工作了。

    Matteo Iannacone & Luca G. Guidotti

    目前已批准的乙型肝炎病毒 (HBV) 慢性感染治疗方法仅限于两种主要类型：注射干扰素（一种通常由免疫系统产生以对抗感染的物质）和核苷或核苷酸类似物 (NUC)。 NUC 是一种耐受性良好的药物，可口服以有效抑制病毒复制，是大多数国家慢性 HBV 的主要治疗方法。然而，与抗 HIV 药物类似，NUC 很少根除病毒，迫使 HBV 感染者接受终生治疗以防止肝病的危险复发。

HBV 领域的一个普遍教条是从其他慢性感染的研究中借鉴而来的。它断言，减少血液或肝脏中的病毒抗原——尤其是乙型肝炎表面抗原，或 HBsAg——可能会唤醒称为 T 细胞的免疫细胞，以便它们对抗病毒并清除慢性感染。因此，几种降低循环中病毒抗原水平或减少其在肝脏中产生的治疗方法已经进入临床，无论是单独使用还是与 NUC 或干扰素联合使用。

自然展望的一部分：乙型肝炎

但最近的调查结果使人们对这种策略产生了怀疑。事实上，过去两年的研究表明，循环中的 HBsAg 水平不会影响可以应对 HBV3,4 的 T 细胞的数量或功能。此外，对小鼠的研究表明，从血液中去除 HBsAg 并不能改善对 HBV5 特异性的 T 细胞反应的功能。减少肝脏中病毒抗原的产生也可能不起作用——将肝细胞上的抗原减少多达 50 倍的小鼠实验未能引发具有潜在抗病毒活性的 T 细胞反应 6,7。在此基础上，我们预测减少抗原的策略最多只能部分或暂时恢复慢性 HBV 患者的免疫系统，而不是根除病毒。

因此，我们认为减少抗原不足以激发对持续性 HBV 感染的显着免疫控制。为了开发一种对慢性 HBV 有效的疗法，有必要考虑免疫刺激方法，考虑到 HBV 持续存在的环境和条件的几个关键特性。

这些特点中的第一个是肝脏中的多孔血液供应，每分钟约有三分之一的血细胞通过肝脏缓慢移动。这有助于循环 T 细胞轻松识别底层肝细胞上的 HBV 抗原，即使不离开血管6。

第二个特点是，当 T 细胞第一次到达肝脏并识别肝细胞上的 HBV 抗原时，它们通常无法抵抗病毒。发生这种情况是因为肝细胞无法为 T 细胞提供激活和分化的特定信号。这种反应迟钝也被认为是为什么 HBV 和其他主要影响肝脏的病毒（如丙型肝炎）能够建立终身感染。

第三，HBV 感染持续时间长，通常跨越数十年，似乎削弱了 HBV 特异性 T 细胞的抗病毒潜力3。事实上，这种持久性对疾病进程的影响比循环和肝脏抗原的相对丰度更大。

更多来自自然展望

这些特性提示了开发 HBV 疗法的其他方法。例如，治疗性疫苗的使用可能会刺激专业的抗原呈递细胞（如树突状细胞）吸收 HBV 抗原并迁移到引流注射区域的淋巴结。在那里，树突状细胞可能会为未遇到抗原的 HBV 特异性 T 细胞（称为初始 T 细胞）提供肝细胞无法提供的激活信号，从而允许“效应”T 细胞分化、进入肝脏并对抗 HBV。在另一种方法中，治疗性疫苗可以与免疫系统调节剂结合，使幼稚 T 细胞能够从称为枯否细胞的特殊肝细胞接收适当的信号。这对于在遇到疫苗产生的抗原之前到达肝脏的幼稚 T 细胞特别有帮助。最后，治疗性疫苗和免疫调节剂可能对患有 HBV 的年轻人最有效，与成年人不同，他们的 HBV 特异性 T 细胞的数量和功能不会因长时间接触抗原而减少。
将减少抗原的方法与治疗性疫苗相结合，在临床前模型中取得了有希望的结果。使用白细胞介素 2 等免疫调节剂也是如此，它允许幼稚 T 细胞在识别特定枯否细胞亚群上的抗原后获得有效的抗病毒活性 6,9。因此，对 HBV 感染的长期抑制和免疫控制很可能需要将治疗性疫苗和免疫调节剂与直接作用的抗病毒药物相结合——不仅是批准的 NUC，还包括作为抗 HBV 有效武器的衣壳组装抑制剂。

由于安全和监管问题以及高成本，复杂的联合疗法极难开发。因此，对正在进行的减少抗原药物的临床研究进行仔细和快速的评估至关重要。这将使我们能够抓住机会，设计出新的、更科学的组合来对抗这种令人烦恼的病毒。

自然 603, S49 (2022)

doi：https://doi.org/10.1038/d41586-022-00813-0

StephenW

Developing a cure for chronic hepatitis B requires a fresh approach
The prevailing dogma for drug development is insufficient; it’s time to recentre efforts around the immune system.

    Matteo Iannacone & Luca G. Guidotti

    Approved treatments for chronic infections of hepatitis B virus (HBV) are currently limited to two main types: injections of interferon, a substance normally produced by the immune system to fight infections, and nucleoside or nucleotide analogues (NUCs). NUCs are well-tolerated drugs that can be taken orally to potently suppress virus replication, and are the main therapy for chronic HBV in most countries. In a similar way to anti-HIV drugs, however, NUCs seldom eradicate the virus, forcing people with HBV to have lifelong treatment to prevent dangerous recurrences of liver disease1.

A prevailing dogma in the HBV field has been borrowed from studies of other chronic infections. It asserts that reducing viral antigens in the blood or liver — especially the hepatitis B surface antigen, or HBsAg — might awaken immune cells called T cells so that they will fight the virus and clear the chronic infection2. Accordingly, several therapeutic approaches that either reduce levels of viral antigens in the circulation or decrease their production in the liver have already reached the clinic, both alone and in combination with NUCs or interferon1.

Part of Nature Outlook: Hepatitis B

But recent findings are casting doubt on this strategy. Indeed, studies in the past two years have demonstrated that HBsAg levels in the circulation do not affect the magnitude or the function of T cells that could tackle HBV3,4. Moreover, research in mice has shown that removing HBsAg from the blood does not improve the function of T-cell responses that are specific to HBV5. Reducing the production of viral antigens in the liver might not work, either — mouse experiments that decreased antigens on liver cells by up to 50-fold failed to elicit T-cell responses that had potential antiviral activity6,7. On this basis, we predict that antigen-reduction strategies will, at best, provide only partial or transient restoration of the immune system in people with chronic HBV, rather than eradicating the virus.

We therefore think that reducing antigens is not enough to provoke significant immune control of persistent HBV infection. To develop a therapy that is effective against chronic HBV, it will be necessary to consider immune-stimulating approaches that take into account several key peculiarities of the environment and conditions in which HBV persists.

The first of those peculiarities is the porous blood supply in the liver, through which about one-third of all blood cells move slowly every minute. This helps circulating T cells to recognize HBV antigens on underlying liver cells easily, even without exiting the blood vessels6.

A second peculiarity is that when T cells reach the liver and recognize HBV antigens on liver cells for the first time, they typically become incapable of fighting the virus. This happens because the liver cells fail to provide the T cells with specific signals for activation and differentiation6. This unresponsiveness is also thought to be why HBV and other viruses that affect mainly the liver, such as hepatitis C, are able to establish lifelong infections.

Third, the long duration of HBV infection, often spanning decades, seems to weaken the antiviral potential of HBV-specific T cells3. Indeed, this persistence has a greater effect on the course of the disease than does the relative abundance of circulating and liver antigens.

More from Nature Outlooks

These peculiarities suggest other ways to develop therapies for HBV. For instance, the use of therapeutic vaccines might stimulate professional antigen-presenting cells (such as dendritic cells) to take up HBV antigens and migrate to lymph nodes draining the injection area. There, dendritic cells might provide HBV-specific T cells that have not encountered antigens (known as naive T cells) with the activation signals that liver cells cannot supply, allowing ‘effector’ T cells to differentiate, travel to the liver and fight HBV. In another approach, therapeutic vaccines could be combined with immune-system modulators in a manner that would enable naive T cells to receive appropriate signals from specialized liver cells called Kupffer cells. This could be particularly helpful for naive T cells that reach the liver before they have encountered vaccine-generated antigens. Lastly, therapeutic vaccines and immunomodulators might work best in young people with HBV, in whom the number and function of HBV-specific T cells are not reduced by prolonged antigen exposure, unlike in adults8.
Combining antigen-reducing approaches with therapeutic vaccines has yielded promising results in preclinical models7. The same is true for the use of immunomodulators such as interleukin-2, which allow naive T cells to acquire potent antiviral activity after recognizing antigens on a specific subset of Kupffer cells6,9. Thus, long-term suppression and immune control of HBV infection could well require a combination of therapeutic vaccines and immunomodulators with direct-acting antivirals — not just approved NUCs, but also the capsid-assembly inhibitors that are emerging as potent weapons against HBV.

Complex combination therapies are extremely difficult to develop, because of safety and regulatory issues as well as high costs. It is therefore paramount that ongoing clinical studies of antigen-reducing drugs are assessed carefully and quickly. This will allow us to seize the opportunity to design new and more scientifically sound combinations to fight this vexing virus.

Nature 603, S49 (2022)

doi: https://doi.org/10.1038/d41586-022-00813-0