HIV-1 replication.
HIV-1 replication.
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DOI：
10.1023/a:1021070512287
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发表时间：
2001-11-01
期刊：
影响因子：
--
通讯作者：
Freed, Eric O.
中科院分区：
文献类型：
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作者：
Freed, Eric O.
总的来说，包括HIV-1在内的慢病毒的复制周期与其他逆转录病毒的复制周期非常相似。然而，艾滋病毒复制有许多独特的方面；例如，HIV和SIV靶向受体和辅助受体不同于其他逆转录病毒使用的受体和辅助受体。慢病毒编码一些典型的“简单”逆转录病毒基因组没有编码的调节蛋白和辅助蛋白。从基因治疗的角度来看，尤其令人感兴趣的是，慢病毒具有高效感染某些类型的未分裂细胞的能力。本章在重申第一章中讨论的某些观点的同时，将试图集中讨论艾滋病毒-1复制所特有的问题。HIV-1基因组编码所有具有复制能力的逆转录病毒共有的主要结构和非结构蛋白(图1和第1章)。从基因组的5‘端到3’端，发现了GAG(组特异性抗原)、POL(聚合酶)和env(包膜糖蛋白)基因。Gag基因编码一种多蛋白前体，其名称Pr55Gag是基于其分子量。Pr55Gag被病毒蛋白酶(PR)切割成成熟的Gag蛋白基质(也称为MA或p17)、衣壳(CA或p24)、核衣壳(NC或p7)和p6。Pr55Gag处理时还产生了两个间隔肽p2和p1。POL编码的酶最初是作为大的多蛋白前体Pr160GagPol的一部分合成的，Pr160GagPol的合成是Pr55Gag翻译过程中罕见的移码事件的结果。病毒PR从Pr160GagPol中切割出PR、逆转录酶(RT)和整合酶(IN)等Pol编码的酶。包膜(Env)糖蛋白也被合成为多蛋白前体(图1)。与被病毒PR切割的Gag和Pol前体不同，Env前体，即gp160，在Env运输到细胞表面的过程中由细胞蛋白酶处理。Gp160处理导致产生表面(SU)环境糖蛋白gp120和跨膜(TM)糖蛋白gp41。Gp120包含与受体和辅受体相互作用的决定因素，而gp41不仅将gp120/gp41复合体锚定在膜上(图2)，而且还包含在病毒进入过程中催化病毒和宿主脂双层之间的膜融合反应的结构域。对大量病毒分离株的env序列进行比较发现，gp120由5个保守区(C1-C5)和5个高变区(V1-V5)组成。可变区往往位于二硫键连接的环中。Gp41由三个主要结构域组成：胞外结构域(它包含膜融合所必需的决定因素)、跨膜锚定序列和细胞质尾部。除了Gag、Poll和env基因外，HIV-1还编码一些调节蛋白和辅助蛋白。TAT对HIV-1LTR转录起关键作用，而REV在病毒RNA从细胞核到细胞质的运输中起着重要作用。VPU、Vif、Vpr和Nef被称为“辅助”或“辅助”蛋白，以反映病毒复制并不统一需要的事实。这些非常有趣的蛋白质的功能将在本章末尾更详细地讨论。艾滋病毒复制在一系列事件中进行，可分为两个总体阶段：“早期”和“晚期”(图3)。尽管有些事件以协调一致或同时发生的方式发生，但可以最简单地将复制周期视为以有序、循序渐进的方式进行。在本章中，将考虑病毒复制的每个步骤；可以从引用的更详细的综述和主要参考文献中获得更多信息。
In general terms, the replication cycle of lentiviruses, including HIV-1, closely resembles that of other retroviruses. There are, however, a number of unique aspects of HIV replication; for example, the HIVs and SIVs target receptors and coreceptors distinct from those used by other retroviruses. Lentiviruses encode a number of regulatory and accessory proteins not encoded by the genomes of the prototypical "simple" retroviruses. Of particular interest from the gene therapy perspective, lentiviruses possess the ability to productively infect some types of non-dividing cells. This chapter, while reiterating certain points discussed in Chapter 1, will attempt to focus on issues unique to HIV-1 replication. The HIV-1 genome encodes the major structural and non-structural proteins common to all replication-competent retroviruses (Fig. 1, and Chapter 1). From the 5'- to 3'-ends of the genome are found the gag (for group-specific antigen), pol (for polymerase), and env (for envelope glycoprotein) genes. The gag gene encodes a polyprotein precursor whose name, Pr55Gag, is based on its molecular weight. Pr55Gag is cleaved by the viral protease (PR) to the mature Gag proteins matrix (also known as MA or p17), capsid (CA or p24), nucleocapsid (NC or p7), and p6. Two spacer peptides, p2 and p1, are also generated upon Pr55Gag processing. The pol-encoded enzymes are initially synthesized as part of a large polyprotein precursor, Pr160GagPol, whose synthesis results from a rare frameshifting event during Pr55Gag translation. The individual pol-encoded enzymes, PR, reverse transcriptase (RT), and integrase (IN), are cleaved from Pr160GagPol by the viral PR. The envelope (Env) glycoproteins are also synthesized as a polyprotein precursor (Fig. 1). Unlike the Gag and Pol precursors, which are cleaved by the viral PR, the Env precursor, known as gp160, is processed by a cellular protease during Env trafficking to the cell surface. gp160 processing results in the generation of the surface (SU) Env glycoprotein gp120 and the transmembrane (TM) glycoprotein gp41. gp120 contains the determinants that interact with receptor and coreceptor, while gp41 not only anchors the gp120/gp41 complex in the membrane (Fig. 2), but also contains domains that are critical for catalyzing the membrane fusion reaction between viral and host lipid bilayers during virus entry. Comparison of env sequences from a large number of virus isolates revealed that gp120 is organized into five conserved regions (C1-C5) and five highly variable domains (V1-V5). The variable regions tend to be located in disulfide-linked loops. gp41 is composed of three major domains: the ectodomain (which contains determinants essential for membrane fusion), the transmembrane anchor sequence, and the cytoplasmic tail. In addition to the gag, pol, and env genes, HIV-1 also encodes a number of regulatory and accessory proteins. Tat is critical for transcription from the HIV-1 LTR and Rev plays a major role in the transport of viral RNAs from the nucleus to the cytoplasm. Vpu, Vif, Vpr and Nef have been termed "accessory" or "auxiliary" proteins to reflect the fact that they are not uniformly required for virus replication. The functions of these very interesting proteins will be discussed in more detail at the end of this chapter. HIV replication proceeds in a series of events that can be divided into two overall phases: "early" and "late" (Fig. 3). Although some events occur in a concerted or simultaneous fashion, the replication cycle can be viewed most simply as proceeding in an ordered, step-wise manner. In this chapter, each step in virus replication will be considered; additional information can be obtained from the more detailed reviews and primary references that are cited.