Pathogenesis and Treatment of HIV Infection

炎症和凝血的基线标志物已被证明是HIV感染患者不良结局的有力预测因子。 在随机分配到立即与延迟开始抗逆转录病毒治疗的HIV感染患者的比较中，D-二聚体水平在开始治疗后显著下降，但白细胞介素-6或高敏C反应蛋白水平没有显著下降。 HIV感染与免疫系统的显著激活有关。 这种活化差异性地影响CD 4和CD 8 T细胞。 使用溴脱氧尿苷在体内标记，我们能够研究的CD 4和CD 8 T细胞池内的不同亚群的动力学及其与病毒载量和CD 4耗竭的关系。 发现HIV病毒载量是CD 8 T细胞的记忆和幼稚亚群以及CD 4 T细胞的记忆亚群增殖的驱动力，而发现CD 4耗竭是幼稚CD 4 T细胞增殖的驱动力。 IL-15是参与免疫系统调节的细胞因子，对NK和CD 8 T细胞的增殖和活化具有特别显著的作用。 IL-15受体利用其自身独特的α链和与IL-2相同的β链和γ链。 为了准备在HIV感染患者中进行人体试验，在良好生产规范（GMP）的条件下生产重组人IL-15。 在一项涉及24只恒河猴的安全性研究中，将其随机分配至对照组或不同的IL-15静脉推注剂量组，观察到的主要毒性是似乎继发于细胞再分布的一过性中性粒细胞减少症。 观察到外周血CD 4、CD 8和NK细胞池的大小一过性增加2-4倍。 HIV-1的进化是通过研究两个同卵双胞胎中病毒准种的变化来研究的，这两个同卵双胞胎在出生时就感染了来自共享输血源的HIV-1人群。 尽管相同的宿主遗传背景的双胞胎和相同的感染源和HIV-1感染的时间，由此产生的HIV人群不同的遗传多样性，生长速度，重组率和类型的选择压力表明随机表观遗传选择的显着影响早期HIV-1感染动态。 利用人细胞系，发现任何质粒DNA的转染都与III型IFN（干扰素-λ）的诱导有关。 这种诱导被发现是由胞质蛋白Ku 70诱导，并由另一种胞质蛋白Ku 80调节。 已经开发出能够使用抗逆转录病毒治疗史、基线CD 4计数、病毒载量和病毒基因型预测HIV感染患者对新药物组合的病毒学应答的计算模型。 这些模型已被用于开发一种在线治疗选择工具，上级标准工具，基因型敏感性评分。 在一项回顾性研究中，医生发现，使用该系统会导致在大约1/3的病例中考虑并可能最终选择不同的治疗方案。 在这些情况下，预测模型选择的方案比选择的方案提供更好的病毒学应答。

Baseline markers of inflammation and coagulation have been shown to be powerful predictors of adverse outcomes in patients with HIV infection. In a comparison of patients with HIV infection randomized to immediate versus delayed initiation of antiretroviral therapy levels of D-dimer, but not interleukin-6 or high sensitivity C-reactive protein declined significantly after starting therapy. HIV infection is associated with a pronounced activation of the immune system. This activation differentially affects CD4 and CD8 T cells. Using in vivo labeling with bromodeoxyuridine we were able to study the kinetics of different subsets within the CD4 and CD8 T cell pools and their relationships to viral load and CD4 depletion. HIV viral load was found to be a driving force behind the proliferation of memory and naive subsets of CD8 T cells and the memory subset of CD4 T cells while CD4 depletion was found to be the driving force behind naive CD4 T cell proliferation. IL-15 is a cytokine involved in the regulation of the immune system with particularly striking effects on the proliferation and activation of NK and CD8 T cells. The IL-15 receptor utilizes its own unique alpha chain and the same beta- and gamma-chains as IL-2. To prepare for human trials in patients with HIV infection, recombinant human IL-15 was produced under conditions of good manufacturing practices (GMP). In a safety study involving 24 rhesus macaques randomized to control or different iv bolus doses of IL-15, the major toxicity that was observed was transient neutropenia that appeared to be secondary to redistribution of cells. Transient 2-4 fold increases in the size of the peripheral blood CD4, CD8 and NK cell pools were noted. HIV-1 evolution was examined by studying changes in viral quasi-species in two monozygotic twins infected at birth with an HIV-1 population from a shared blood transfusion source. Despite the identical host genetic background of the twins and the identical source of infection and timing of HIV-1 infection, the resulting HIV populations differed in genetic diversity, growth rate, recombination rate and types of selective pressures indicating the significant impact of random epigenetic selection in early HIV-1 infection dynamics. Utilizing a human cell line it was discovered that the transfection of any plasmid DNA was associated with induction of type III IFN (interferon-lambda). This induction was found to be induced by the cytosolic protein Ku70 and regulated by another cytosolic protein Ku80. Computational models have been developed that are able to predict the virologic response of patients with HIV infection to new drug combinations using antiretroviral treatment history, baseline CD4 count, viral load and viral genotype. These models have been used to develop an online treatment selection tool that is superior to that of the standard tool, a genotypic sensitivity score. In a retrospective study, physicians found that the use of this system would have led to the consideration and likely eventually selection of different treatment regimens in approximately 1/3 of cases. In those instances, the regimens selected by the model were predicted to provide better virologic responses than the regimens that had been chosen.