Department of Laboratory Medicine, Lund University, Lund, Sweden.
PLoS Pathog. 2010 Sep 2;6(9):e1001084. doi: 10.1371/journal.ppat.1001084.
Neutralizing antibodies (NAb) able to react to heterologous viruses are generated during natural HIV-1 infection in some individuals. Further knowledge is required in order to understand the factors contributing to induction of cross-reactive NAb responses. Here a well-established model of experimental pathogenic infection in cynomolgus macaques, which reproduces long-lasting HIV-1 infection, was used to study the NAb response as well as the viral evolution of the highly neutralization-resistant SIVmac239. Twelve animals were infected intravenously with SIVmac239. Antiretroviral therapy (ART) was initiated ten days post-inoculation and administered daily for four months. Viral load, CD4(+) T-cell counts, total IgG levels, and breadth as well as strength of NAb in plasma were compared simultaneously over 14 months. In addition, envs from plasma samples were sequenced at three time points in all animals in order to assess viral evolution. We report here that seven of the 12 animals controlled viremia to below 10(4) copies/ml of plasma after discontinuation of ART and that this control was associated with a low level of evolutionary divergence. Macaques that controlled viral load developed broader NAb responses early on. Furthermore, escape mutations, such as V67M and R751G, were identified in virus sequenced from all animals with uncontrolled viremia. Bayesian estimation of ancestral population genetic diversity (PGD) showed an increase in this value in non-controlling or transient-controlling animals during the first 5.5 months of infection, in contrast to virus-controlling animals. Similarly, non- or transient controllers displayed more positively-selected amino-acid substitutions. An early increase in PGD, resulting in the generation of positively-selected amino-acid substitutions, greater divergence and relative high viral load after ART withdrawal, may have contributed to the generation of potent NAb in several animals after SIVmac239 infection. However, early broad NAb responses correlated with relatively preserved CD4(+) T-cell numbers, low viral load and limited viral divergence.
中和抗体（NAb）能够与异源病毒反应，在一些个体的自然 HIV-1 感染过程中产生。为了了解诱导交叉反应性 NAb 反应的因素，还需要进一步的知识。在此，我们使用已建立的食蟹猴实验性致病性感染模型，该模型可复制长期 HIV-1 感染，用于研究 NAb 反应以及高度中和抗性 SIVmac239 的病毒进化。12 只动物经静脉感染 SIVmac239。感染后十天开始给予抗逆转录病毒治疗（ART），持续四个月。在 14 个月内同时比较病毒载量、CD4(+) T 细胞计数、总 IgG 水平以及血浆中 NAb 的广度和强度。此外，为了评估病毒进化，在所有动物的三个时间点对来自血浆样本的 env 进行测序。我们在此报告，12 只动物中的 7 只在停止 ART 后将病毒血症控制在 10(4)拷贝/ml 以下，这种控制与低水平的进化分歧有关。控制病毒载量的猕猴早期产生了更广泛的 NAb 反应。此外，在所有未控制病毒血症的动物的病毒序列中鉴定出了逃逸突变，如 V67M 和 R751G。非控制或短暂控制动物在感染的前 5.5 个月内，与病毒控制动物相比，祖先种群遗传多样性（PGD）的贝叶斯估计值增加。同样，非控制或短暂控制者显示出更多的正选择氨基酸取代。PGD 的早期增加导致正选择氨基酸取代的产生、更大的分歧和 ART 停药后相对高的病毒载量，可能有助于在 SIVmac239 感染后，若干动物产生有效的 NAb。然而，早期广泛的 NAb 反应与相对保存的 CD4(+) T 细胞数量、低病毒载量和有限的病毒分歧相关。
