HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility
HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility
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DOI：
10.1128/jvi.01604-19
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发表时间：
2020-01-01
影响因子：
5.4
通讯作者：
Sagar, Manish
中科院分区：
文献类型：
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作者：
Registre, Ludy;Moreau, Yvetane;Sagar, Manish
在临床试验中，HIV-1广泛中和抗体（bnAbs）可有效降低血浆病毒血症并延迟病毒重新出现。治疗前存在较低的中和敏感性菌株会降低这些基于抗体的治疗的疗效，但中和敏感性通常无法单独通过序列分析预测。我们发现，在某些但不是全部情况下，表型确认的CXCR 4利用菌株的中和敏感性，特别是对可变环3（V3环）定向bnAb的中和敏感性低于完全利用CCR 5的菌株。同源性建模表明，主要V3环bnAb表位在使用CCR 5和CXCR 4的菌株中同样可接近，尽管仅使用CXCR 4的变体具有干扰CCR 5受体相互作用的V3环突起。同源性建模还显示，在一些但不是全部中和敏感性降低的包膜中，V1环方向干扰V3环定向bnAb结合。因此，可能存在共受体使用限制和不同bnAb亲和性的不同结构原因。重要的是，我们表明，携带包膜的个体使用CXCR 4或更大的预测V1环干扰的可能性更高，在用V3环bnAb治疗后，病毒反弹更快，血浆病毒血症的最大降幅更低。知识的受体的使用和同源性模型可能是有用的，在开发未来的算法，预测治疗效果与V3环bnAbs.IMPORTANCE HIV-1广泛中和抗体（bnAb）疗法的疗效可能会受到损害的易感性较低的变体的预先存在。需要基于序列的方法来预测预处理变体中和敏感性。专门使用CXCR 4受体而不是CCR 5受体的HIV-1毒株对中和敏感性较低，特别是在一些但不是所有情况下对可变环3（V3环）bnAb。虽然不能利用CCR 5受体映射到包膜V3环中的预测突起，但该病毒决定簇不直接影响V3环bnAb灵敏度。同源性建模预测，在某些情况下，包膜V1环和抗体之间的接触会影响V3环bnAb的易感性。在治疗前包膜中，使用CXCR 4的概率增加和预测的V1干扰更大分别与V3 loop bnAb治疗后病毒反弹更快和血浆病毒水平下降更小相关。受体使用信息和同源性模型可用于预测V3环bnAb治疗功效。
In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia and delay virus reemergence. The presence of less neutralization-susceptible strains prior to treatment decreases the efficacy of these antibody-based treatments, but neutralization sensitivity often cannot be predicted by sequence analysis alone. We found that phenotypically confirmed CXCR4-utilizing strains are less neutralization sensitive, especially to variable loop 3 (V3 loop)-directed bnAbs, than exclusively CCR5-utilizing strains in some, but not all, cases. Homology modeling suggested that the primary V3 loop bnAb epitope is equally accessible among CCR5- and CXCR4-using strains, although variants that exclusively use CXCR4 have V3 loop protrusions that interfere with CCR5 receptor interactions. Homology modeling also showed that among some, but not all, envelopes with decreased neutralization sensitivity, V1 loop orientation interfered with V3 loop-directed bnAb binding. Thus, there are likely different structural reasons for the coreceptor usage restriction and the different bnAb susceptibilities. Importantly, we show that individuals harboring envelopes with higher likelihood of using CXCR4 or greater predicted V1 loop interference have faster virus rebound and a lower maximum decrease in plasma viremia, respectively, after treatment with a V3 loop bnAb. Knowledge of receptor usage and homology models may be useful in developing future algorithms that predict treatment efficacy with V3 loop bnAbs.IMPORTANCE The efficacy of HIV-1 broadly neutralizing antibody (bnAb) therapies may be compromised by the preexistence of less susceptible variants. Sequence-based methods are needed to predict pretreatment variants neutralization sensitivities. HIV-1 strains that exclusively use the CXCR4 receptor rather than the CCR5 receptor are less neutralization susceptible, especially to variable loop 3 (V3 loop) bnAbs in some, but not all, instances. While the inability to utilize the CCR5 receptor maps to a predicted protrusion in the envelope V3 loop, this viral determinant does not directly influence V3 loop bnAb sensitivity. Homology modeling predicts that contact between the envelope V1 loop and the antibody impacts V3 loop bnAb susceptibility in some cases. Among pretreatment envelopes, increased probability of using CXCR4 and greater predicted V1 interference are associated with faster virus rebound and a smaller decrease in the plasma virus level, respectively, after V3 loop bnAb treatment. Receptor usage information and homology models may be useful for predicting V3 loop bnAb therapy efficacy.