Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7.
Transmitted/founder and chronic subtype C HIV-1 use CD4 and CCR5 receptors with equal efficiency and are not inhibited by blocking the integrin α4β7.
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DOI：
10.1371/journal.ppat.1002686
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发表时间：
2012
期刊：
影响因子：
6.7
通讯作者：
Doms RW
中科院分区：
文献类型：
--
作者：
Parrish NF;Wilen CB;Banks LB;Iyer SS;Pfaff JM;Salazar-Gonzalez JF;Salazar MG;Decker JM;Parrish EH;Berg A;Hopper J;Hora B;Kumar A;Mahlokozera T;Yuan S;Coleman C;Vermeulen M;Ding H;Ochsenbauer C;Tilton JC;Permar SR;Kappes JC;Betts MR;Busch MP;Gao F;Montefiori D;Haynes BF;Shaw GM;Hahn BH;Doms RW
人类免疫缺陷病毒1型（HIV-1）的性传播通常是由单一传播/创始者（T/F）病毒的生产性感染引起的，表明存在严格的粘膜瓶颈。了解克服这一瓶颈的病毒特征可能对HIV-1疫苗设计和其他预防策略具有重要意义。大多数T/F病毒使用CCR 5感染靶细胞，并且一些编码的包膜糖蛋白（Envs）比慢性病毒的Envs含有更少的潜在N-连接糖基化位点和更短的V1/V2可变环。此外，据报道，某些传播的Env的gp 120亚基与肠道归巢整合素α4β7结合，可能增强病毒进入和细胞间传播。在这里，我们试图确定亚型C T/F病毒，这是全球大多数新的HIV-1感染的原因，是否具有增加其传播适应性的生物学特性，包括优先α4β7参与。使用单基因组扩增，我们生成了T/F（n = 20）和慢性（n = 20）Env构建体以及全长T/F（n = 6）和慢性（n = 4）感染性分子克隆（IMC）。 我们发现，T/F和慢性对照Envs在使用CD 4和CCR 5的效率方面没有区别。两组Env也表现出相同的CD 4 + T细胞亚群嗜性，并显示出对CD 4结合位点（CD 4 bs）抗体中和的相似敏感性。最后，饱和浓度的抗α4β7抗体未能抑制T/F以及慢性对照病毒的感染和复制，尽管组织培养适应菌株SF 162的生长受到适度损害。这些结果表明，与粘膜HIV-1感染相关的群体瓶颈并不是由于选择了更有效地利用α4β7、CD 4或CCR 5的T/F病毒。全世界大多数新的HIV-1感染是由C亚型病毒的性传播引起的，这种病毒在亚洲和南部非洲流行。虽然慢性感染者携带一组遗传多样性的病毒，但大多数新感染是由单一变体建立的，称为传播/创始者（T/F）病毒。这就提出了一个问题，即某些病毒变体是否具有特殊的特性，使它们能够更有效地克服传播瓶颈。病毒包膜（Env）与整合素α4β7的优先结合已被假设为传播病毒的一个重要特征。在这里，我们比较了来自C亚型病毒的Envs，这些病毒传播给慢性感染中流行的病毒，以获得利用α4β7，CD 4和CCR 5进入细胞和复制的效率。我们发现，传播性和慢性Env以相同的效率接合CD 4和CCR 5，并且阻断Env和α4β7之间的相互作用不能抑制T/F以及对照病毒的复制。虽然寻找传播适应性的决定因素仍然是一个重要目标，但优先的CD 4、CCR 5或α4β7相互作用似乎并不能代表T/F病毒的显著特征。
Sexual transmission of human immunodeficiency virus type 1 (HIV-1) most often results from productive infection by a single transmitted/founder (T/F) virus, indicating a stringent mucosal bottleneck. Understanding the viral traits that overcome this bottleneck could have important implications for HIV-1 vaccine design and other prevention strategies. Most T/F viruses use CCR5 to infect target cells and some encode envelope glycoproteins (Envs) that contain fewer potential N-linked glycosylation sites and shorter V1/V2 variable loops than Envs from chronic viruses. Moreover, it has been reported that the gp120 subunits of certain transmitted Envs bind to the gut-homing integrin α4β7, possibly enhancing virus entry and cell-to-cell spread. Here we sought to determine whether subtype C T/F viruses, which are responsible for the majority of new HIV-1 infections worldwide, share biological properties that increase their transmission fitness, including preferential α4β7 engagement. Using single genome amplification, we generated panels of both T/F (n = 20) and chronic (n = 20) Env constructs as well as full-length T/F (n = 6) and chronic (n = 4) infectious molecular clones (IMCs). We found that T/F and chronic control Envs were indistinguishable in the efficiency with which they used CD4 and CCR5. Both groups of Envs also exhibited the same CD4+ T cell subset tropism and showed similar sensitivity to neutralization by CD4 binding site (CD4bs) antibodies. Finally, saturating concentrations of anti-α4β7 antibodies failed to inhibit infection and replication of T/F as well as chronic control viruses, although the growth of the tissue culture-adapted strain SF162 was modestly impaired. These results indicate that the population bottleneck associated with mucosal HIV-1 acquisition is not due to the selection of T/F viruses that use α4β7, CD4 or CCR5 more efficiently. Most new HIV-1 infections worldwide are caused by the sexual transmission of subtype C viruses, which are prevalent in Asia and southern Africa. While chronically infected individuals harbor a genetically diverse set of viruses, most new infections are established by single variants, termed transmitted/founder (T/F) viruses. This raises the question whether certain viral variants have particular properties allowing them to more efficiently overcome the transmission bottleneck. Preferential binding of the viral envelope (Env) to the integrin α4β7 has been hypothesized as one important feature of transmitted viruses. Here, we compared Envs from subtype C viruses that were transmitted to those that were prevalent in chronic infections for efficiency in utilizing α4β7, CD4 and CCR5 for cell entry and replication. We found that transmitted and chronic Envs engaged CD4 and CCR5 with equal efficiency, and that blocking the interaction between Env and α4β7 failed to inhibit replication of T/F as well as control viruses. While the search for determinants of transmission fitness remains an important goal, preferential CD4, CCR5 or α4β7 interactions do not appear to represent distinguishing features of T/F viruses.
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影响因子：
3.7
作者：
Asmal M;Hellmann I;Liu W;Keele BF;Perelson AS;Bhattacharya T;Gnanakaran S;Daniels M;Haynes BF;Korber BT;Hahn BH;Shaw GM;Letvin NL
通讯作者：
Letvin NL
影响因子：
6.4
作者：
Chalmet, Kristen;Dauwe, Kenny;Verhofstede, Chris
通讯作者：
Verhofstede, Chris
DOI：
10.1073/pnas.94.5.1925
发表时间：
1997-03-04
影响因子：
11.1
作者：
Bleul, CC;Wu, LJ;Mackay, CR
通讯作者：
Mackay, CR
影响因子：
56.9
作者：
BURTON, DR;PYATI, J;BARBAS, CF
通讯作者：
BARBAS, CF
DOI：
10.1073/pnas.0911796106
发表时间：
2009-12-08
影响因子：
11.1
作者：
Cicala, Claudia;Martinelli, Elena;Arthos, James
通讯作者：
Arthos, James