Selhorst Philippe, Combrinck Carina, Ndabambi Nonkululeko, Ismail Sherazaan D, Abrahams Melissa-Rose, Lacerda Miguel, Samsunder Natasha, Garrett Nigel, Abdool Karim Quarraisha, Abdool Karim Salim S, Williamson Carolyn
Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
Department of Statistical Sciences, Faculty of Science, University of Cape Town, Cape Town, South Africa.
J Virol. 2017 Mar 29;91(8). doi: 10.1128/JVI.01806-16. Print 2017 Apr 15.
The viral genotype has been shown to play an important role in HIV pathogenesis following transmission. However, the viral phenotypic properties that contribute to disease progression remain unclear. Most studies have been limited to the evaluation of Gag function in the context of a recombinant virus backbone. Using this approach, important biological information may be lost, making the evaluation of viruses obtained during acute infection, representing the transmitted virus, a more biologically relevant model. Here, we evaluate the roles of viral infectivity and the replication capacity of viruses from acute infection in disease progression in women who seroconverted in the CAPRISA 004 tenofovir microbicide trial. We show that viral replication capacity, but not viral infectivity, correlates with the set point viral load (Spearman = 0.346; = 0.045) and that replication capacity (hazard ratio [HR] = 4.52; = 0.01) can predict CD4 decline independently of the viral load (HR = 2.9; = 0.004) or protective HLA alleles (HR = 0.61; = 0.36). We further demonstrate that Gag-Pro is not the main driver of this association, suggesting that additional properties of the transmitted virus play a role in disease progression. Finally, we find that although viruses from the tenofovir arm were 2-fold less infectious, they replicated at rates similar to those of viruses from the placebo arm. This indicates that the use of tenofovir gel did not select for viral variants with higher replication capacity. Overall, this study supports a strong influence of the replication capacity in acute infection on disease progression, potentially driven by interaction of multiple genes rather than a dominant role of the major structural gene HIV disease progression is known to differ between individuals, and defining which fraction of this variation can be attributed to the virus is important both clinically and epidemiologically. In this study, we show that the replication capacity of viruses isolated during acute infection predicts subsequent disease progression and drives CD4 decline independently of the viral load. This provides further support for the hypothesis that the replication capacity of the transmitted virus determines the initial damage to the immune system, setting the pace for later disease progression. However, we did not find evidence that the major structural gene drives this correlation, highlighting the importance of other genes in determining disease progression.
病毒基因型已被证明在传播后的HIV发病机制中起重要作用。然而，促成疾病进展的病毒表型特性仍不清楚。大多数研究仅限于在重组病毒骨架背景下评估Gag功能。使用这种方法，重要的生物学信息可能会丢失，使得评估急性感染期间获得的代表传播病毒的病毒成为一个更具生物学相关性的模型。在这里，我们评估了急性感染病毒的感染力和复制能力在CAPRISA 004替诺福韦杀微生物剂试验中血清转化女性疾病进展中的作用。我们发现，病毒复制能力而非病毒感染力与设定点病毒载量相关（斯皮尔曼相关系数 = 0.346；P = 0.045），并且复制能力（风险比[HR] = 4.52；P = 0.01）可以独立于病毒载量（HR = 2.9；P = 0.004）或保护性HLA等位基因（HR = 0.61；P = 0.36）预测CD4下降。我们进一步证明Gag-Pro不是这种关联的主要驱动因素，这表明传播病毒的其他特性在疾病进展中起作用。最后，我们发现尽管来自替诺福韦组的病毒感染力低2倍，但它们与来自安慰剂组的病毒以相似的速率复制。这表明使用替诺福韦凝胶并未选择出具有更高复制能力的病毒变体。总体而言，本研究支持急性感染中的复制能力对疾病进展有强烈影响，这可能是由多个基因的相互作用驱动的，而不是主要结构基因起主导作用。已知HIV疾病进展在个体之间存在差异，确定这种差异的哪一部分可归因于病毒在临床和流行病学上都很重要。在本研究中，我们表明急性感染期间分离的病毒的复制能力可预测随后的疾病进展，并独立于病毒载量驱动CD4下降。这为传播病毒的复制能力决定对免疫系统的初始损害、为后期疾病进展设定步伐这一假设提供了进一步支持。然而，我们没有发现证据表明主要结构基因驱动这种相关性，这突出了其他基因在确定疾病进展中的重要性。
