Impact of Clade, Geography, and Age of the Epidemic on HIV-1 Neutralization by Antibodies
Impact of Clade, Geography, and Age of the Epidemic on HIV-1 Neutralization by Antibodies
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DOI：
10.1128/jvi.01705-14
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发表时间：
2014-11-01
影响因子：
5.4
通讯作者：
Montefiori, David C.
中科院分区：
文献类型：
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作者：
Hraber, Peter;Korber, Bette T.;Montefiori, David C.
中和抗体（nab）是旨在预防获得HIV-1感染的疫苗的高度优先事项。疫苗的有效性将取决于诱导抗体在多大程度上中和循环中的HIV-1变异的全球多样性。通过对遗传和地理上不同的HIV-1 env假型病毒和慢性感染血浆样本的大量研究，我们明确地表明，任何病毒分支的感染通常都会诱导跨分支的nAb反应。尽管如此，当血浆进化支与被测试病毒的进化支相匹配时，中和作用明显更大。与最近发生在亚洲的流行病相比，在非洲南部、美国和欧洲发生的更古老、更多样化的流行病中，这种进化内优势减弱了。最明显的是循环重组型（CRF） 07_BC，这在中国很常见，是研究中分化最小的谱系；其次是更为多样化的亚洲CRF01_AE。我们没有发现证据表明传播/建立病毒通常更容易被中和，因此比慢性病毒更容易成为疫苗接种的目标。gp120 V1V2环的特征，特别是长度、净电荷和n链聚糖的数量，与Env易感性和血浆中和效力相关，其方式与中和逃逸是驱动病毒多样化和血浆中和广度的力量一致。Envs的总体易感性和血浆样品的效力高度预测任何单一病毒-血浆组合的中和结果。这些发现强调了设计和测试候选HIV-1疫苗的重要考虑，这些疫苗旨在产生有效的抗体。一种有效的HIV-1疫苗需要克服病毒的异常变异性，这种变异性在包膜糖蛋白（Env）中最为明显，而包膜糖蛋白是中和抗体（nab）的唯一靶标。HIV-1的不同遗传谱系或分支存在于不同的地区，这在设计和测试候选疫苗时可能需要特别考虑。我们发现nAb对HIV-1感染的反应通常在进化枝上是活跃的，但在进化枝内是最有效的。由于有效的疫苗诱导的nab可能具有这些特性，因此对特定支系或支系组合的最佳覆盖可能需要支系匹配的免疫原。与南部非洲、美国和欧洲相比，中国和泰国等地区的流行时间较晚，病毒的多样性也较低，因此可能更容易实现支系内的最佳覆盖。最后，gp120 （V1V2）的第一和第二高变区特征可能是优化疫苗设计的关键。
Neutralizing antibodies (nAbs) are a high priority for vaccines that aim to prevent the acquisition of HIV-1 infection. Vaccine effectiveness will depend on the extent to which induced antibodies neutralize the global diversity of circulating HIV-1 variants. Using large panels of genetically and geographically diverse HIV-1 Env-pseudotyped viruses and chronic infection plasma samples, we unambiguously show that cross-clade nAb responses are commonly induced in response to infection by any virus clade. Nonetheless, neutralization was significantly greater when the plasma clade matched the clade of the virus being tested. This within-clade advantage was diminished in older, more-diverse epidemics in southern Africa, the United States, and Europe compared to more recent epidemics in Asia. It was most pronounced for circulating recombinant form (CRF) 07_BC, which is common in China and is the least-divergent lineage studied; this was followed by the slightly more diverse Asian CRF01_AE. We found no evidence that transmitted/founder viruses are generally more susceptible to neutralization and are therefore easier targets for vaccination than chronic viruses. Features of the gp120 V1V2 loop, in particular, length, net charge, and number of N-linked glycans, were associated with Env susceptibility and plasma neutralization potency in a manner consistent with neutralization escape being a force that drives viral diversification and plasma neutralization breadth. The overall susceptibility of Envs and potencies of plasma samples were highly predictive of the neutralization outcome of any single virus-plasma combination. These findings highlight important considerations for the design and testing of candidate HIV-1 vaccines that aim to elicit effective nAbs.IMPORTANCE An effective HIV-1 vaccine will need to overcome the extraordinary variability of the virus, which is most pronounced in the envelope glycoproteins (Env), which are the sole targets for neutralizing antibodies (nAbs). Distinct genetic lineages, or clades, of HIV-1 occur in different locales that may require special consideration when designing and testing vaccines candidates. We show that nAb responses to HIV-1 infection are generally active across clades but are most potent within clades. Because effective vaccine-induced nAbs are likely to share these properties, optimal coverage of a particular clade or combination of clades may require clade-matched immunogens. Optimal within-clade coverage might be easier to achieve in regions such as China and Thailand, where the epidemic is more recent and the virus less diverse than in southern Africa, the United States, and Europe. Finally, features of the first and second hypervariable regions of gp120 (V1V2) may be critical for optimal vaccine design.