Russell Charles J
Department of Infectious Diseases, St. Jude Children's Research Hospital, MS 330, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA,
Curr Top Microbiol Immunol. 2014;385:93-116. doi: 10.1007/82_2014_393.
Membrane fusion is not spontaneous. Therefore, enveloped viruses have evolved membrane-fusion mediating glycoproteins that, once activated, refold, and release energy that fuses viral and cellular membranes. The influenza A virus hemagglutinin (HA) protein is a prototypic structural class I viral fusion glycoprotein that, once primed by proteolytic cleavage, is activated by endosomal low pH to form a fusogenic "leash-in-grooves" hairpin structure. Low-pH induced HA protein refolding is an irreversible process, so acid exposure in the absence of a target membrane leads to virus inactivation. The HA proteins of diverse influenza virus subtypes isolated from a variety of species differ in their acid stabilities, or pH values at which irreversible HA protein conformational changes are triggered. Recently, efficient replication of highly pathogenic avian influenza (HPAI) viruses such as H5N1 in avian species has been associated with a relatively high HA activation pH. In contrast, a decrease in H5N1 HA activation pH has been shown to enhance replication and airborne transmission in mammals. Mutations that alter the acid stabilities of H1 and H3 HA proteins have also been discovered that influence the amantadine susceptibilities, replication rates, and pathogenicities of human influenza viruses. An understanding of the role of HA acid stability in influenza virus biology is expected to aid in identifying emerging viruses with increased pandemic potential and assist in developing live attenuated virus vaccines. Acid-induced HA protein activation, which has provided a paradigm for protein-mediated membrane fusion, is now identified as a novel determinant of influenza virus biology.
膜融合并非自发发生。因此，包膜病毒进化出了介导膜融合的糖蛋白，这些糖蛋白一旦被激活，就会重新折叠并释放能量，从而使病毒膜与细胞膜融合。甲型流感病毒血凝素（HA）蛋白是典型的I类结构病毒融合糖蛋白，一旦通过蛋白水解切割引发反应，就会被内体低pH激活，形成促融合的“带槽束缚”发夹结构。低pH诱导的HA蛋白重折叠是一个不可逆的过程，因此在没有靶膜的情况下暴露于酸性环境会导致病毒失活。从各种物种中分离出的不同甲型流感病毒亚型的HA蛋白，其酸稳定性或触发不可逆HA蛋白构象变化的pH值各不相同。最近，高致病性禽流感（HPAI）病毒如H5N1在禽类中的高效复制与相对较高的HA激活pH值有关。相反，已证明H5N1 HA激活pH值的降低会增强其在哺乳动物中的复制和空气传播。还发现了改变H1和H3 HA蛋白酸稳定性的突变，这些突变会影响人流感病毒对金刚烷胺的敏感性、复制速率和致病性。了解HA酸稳定性在流感病毒生物学中的作用，有望有助于识别具有更高大流行潜力的新兴病毒，并协助开发减毒活病毒疫苗。酸诱导的HA蛋白激活为蛋白质介导的膜融合提供了一个范例，现在被确定为流感病毒生物学的一个新决定因素。
