APOBEC3G-induced hypermutation of human immunodeficiency virus type-1 is typically a discrete "all or nothing" phenomenon.
APOBEC3G-induced hypermutation of human immunodeficiency virus type-1 is typically a discrete "all or nothing" phenomenon.
复制标题
DOI：
10.1371/journal.pgen.1002550
复制
发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Iversen AK
中科院分区：
文献类型：
--
作者：
Armitage AE;Deforche K;Chang CH;Wee E;Kramer B;Welch JJ;Gerstoft J;Fugger L;McMichael A;Rambaut A;Iversen AK
人类免疫缺陷病毒（HIV-1）的快速进化使得研究持续的宿主-病原体相互作用成为可能。一个关键的选择性宿主因子是APOBEC 3G（hA 3G），其可以引起HIV正链DNA上广泛的和失活的鸟苷至腺苷（G-to-A）突变（称为超突变）。HIV可以通过病毒蛋白Vif与hA 3G的结合来抑制这种先天性抗病毒防御，但结合效率不同，患者的超突变频率也会波动。一个关键的问题是hA 3G诱导的G到A突变是否总是对病毒致命的，或者它是否可能以亚致死频率发生，从而增加病毒的多样化。我们在体外证明，有限水平的hA 3G活性（即当只有一个hA 3G单位可能对HIV起作用时）产生的超突变频率与患者相似，并通过计算机模拟证明，潜在的非致死性G到A突变率比体外和体内观察到的最低超突变水平低10倍。我们的研究结果表明，即使是一个单一的纳入hA 3G-单位可能会导致广泛的和失活水平的HIV超突变，因此，超突变通常是一个离散的“全有或全无”的现象。因此，抑制Vif和hA 3G之间相互作用的治疗措施可能不会增加病毒多样化，但会扩大感染宿主内高度突变的前病毒的比例。人类细胞具有保守的抗病毒防御系统，可以抵御一系列病毒。这种先天性细胞内防御的一个关键组成部分是APOBEC 3G（hA 3G），它可以在病毒DNA中引起广泛的和失活的G到A突变（称为超突变）。为了避免这种情况，人类免疫缺陷病毒1型（HIV-1）编码一种蛋白质Vif，它可以结合hA 3并阻止其抗病毒作用。然而，Vif并不总是完全有效的，许多HIV-1感染患者携带高度突变的序列。一个关键问题是hA 3G是否也可能产生亚致死水平的G到A突变，这可能会增加病毒的进化，可能会加速疾病的进展。如果发生这种情况，针对Vif的药物和疫苗诱导的CTL反应可能会产生适得其反的效果。我们通过体外、体内和计算机模拟分析表明，hA 3G活性不太可能增强病毒进化。因此，抑制Vif和APOBEC 3G之间相互作用的措施可能只会增加感染宿主中高度突变的灭活HIV序列的比例。
The rapid evolution of Human Immunodeficiency Virus (HIV-1) allows studies of ongoing host–pathogen interactions. One key selective host factor is APOBEC3G (hA3G) that can cause extensive and inactivating Guanosine-to-Adenosine (G-to-A) mutation on HIV plus-strand DNA (termed hypermutation). HIV can inhibit this innate anti-viral defense through binding of the viral protein Vif to hA3G, but binding efficiency varies and hypermutation frequencies fluctuate in patients. A pivotal question is whether hA3G-induced G-to-A mutation is always lethal to the virus or if it may occur at sub-lethal frequencies that could increase viral diversification. We show in vitro that limiting-levels of hA3G-activity (i.e. when only a single hA3G-unit is likely to act on HIV) produce hypermutation frequencies similar to those in patients and demonstrate in silico that potentially non-lethal G-to-A mutation rates are ∼10-fold lower than the lowest observed hypermutation levels in vitro and in vivo. Our results suggest that even a single incorporated hA3G-unit is likely to cause extensive and inactivating levels of HIV hypermutation and that hypermutation therefore is typically a discrete “all or nothing” phenomenon. Thus, therapeutic measures that inhibit the interaction between Vif and hA3G will likely not increase virus diversification but expand the fraction of hypermutated proviruses within the infected host. Human cells have conserved antiviral defense systems, which protect against a range of viruses. A key component of this innate, intra-cellular defense is APOBEC3G (hA3G), which can cause extensive and inactivating G-to-A mutations (termed hypermutation) in viral DNA. To circumvent this, human immunodeficiency virus type-1 (HIV-1) encodes a protein, Vif, which can bind hA3 and prevent its antiviral effects. Vif is however, not always fully efficient, and many HIV-1 infected patients harbor hypermutated sequences. A key question is whether hA3G also might generate sub-lethal levels of G-to-A mutations, which could increase viral evolution, possibly accelerating disease progression. If this were to occur, drugs and vaccine-induced CTL-responses targeting Vif might have counterproductive effects. We show through in vitro, in vivo, and in silico analyses that it is unlikely that hA3G-activity can enhance virus evolution. Thus, measures that inhibit the interaction between Vif and APOBEC3G are likely to only increase the fraction of hypermutated, inactivated HIV sequences in the infected host.
登录
查看更多内容
DOI：
10.1097/00126334-200303010-00003
发表时间：
2003-03-01
影响因子：
3.6
作者：
Hazen, R;Lanier, ER
通讯作者：
Lanier, ER
影响因子：
64.5
作者：
Harris, RS;Bishop, KN;Malim, MH
通讯作者：
Malim, MH
影响因子：
5.4
作者：
Gao, F;Chen, Y;Hui, HX
通讯作者：
Hui, HX
影响因子：
56.9
作者：
Bishop, KN;Holmes, RK;Malim, MH
通讯作者：
Malim, MH
影响因子：
5.4
作者：
Gandhi, Shiv K.;Siliciano, Janet D.;Blankson, Joel N.
通讯作者：
Blankson, Joel N.