Immune System Modeling/HIV

描述(由申请人提供)：对开始抗逆转录病毒治疗后血浆艾滋病毒-1病毒载量下降的数学分析导致了关于艾滋病毒-1感染动态的一些重要见解，但没有治愈。与临床数据分析相结合的建模表明，通过100%有效的治疗，艾滋病毒可以从短期和长期生产性感染细胞群中消除。在这里，我们建议审查与根除艾滋病毒所遇到的障碍有关的一系列问题。我们将提供更好的药物疗效估计，并通过建模来检查非100%有效的药物制度的后果，同时考虑到潜在的药物庇护所。在许多患者中，血浆病毒载量可降至50拷贝/毫升以下，但会出现一过性病毒血症(“BIIP”)，超灵敏分析可检测到持续的低病毒水平。我们建议研究病毒载量在50拷贝/毫升以下的动态变化。我们将检查关于斑点发生的数据，提取关于其幅度和频率的信息，然后通过建模评估潜在的潜在原因，例如，潜伏感染细胞的激活，感染继发的靶细胞的产生，以及药物依从性差。将模拟疫苗接种或感染对免疫系统的扰动影响，以期评估重新填充水库的影响。除了潜伏感染的细胞外，病毒储存库，如附着在滤泡树突状细胞和B细胞表面的病毒，可能会阻碍病毒的根除。我们建议计算这种储存库的寿命，并检查通过补体和Fc受体干扰HIV与细胞表面多价附着的方法。

DESCRIPTION (provided by applicant): The mathematical analysis of plasma HIV-1 viral load decay after the initiation of antiretroviral therapy has led to a number of important insights about the dynamics of HIV-1 infection, but not to a cure. Modeling, coupled to analysis of clinical data, suggested that with 100% effective therapy HIV could be eliminated from both short- and long-lived productively infected cell populations. Here, we propose to examine a set of problems related to the hurdles that have beenencountered to eradicating HIV. We will provide better estimates of drug efficacy and, via modeling,examine the consequences of drug regimes that are not 100% effective, taking into regard potential drug sanctuaries. In many patients plasma viral loads can be driven below 50 copies/ml but transient episodes of viremia ("blips") occur and ultra-sensitive assays detect persistent low levels of virus. We propose to examine the dynamics of viral load changes below 50 copies/ml. We will examine data on the occurrence of blips, extracting information about their amplitude and frequency, and then via modeling evaluate potential underlying causes, e.g., activation of latently infected cells, generation of target cells secondary to infection, and poor drug adherence. Effects of perturbations to the immune system via vaccination or infection will be modeled, with a view toward evaluating the implications for refilling reservoirs. In addition to latently infected cells, viral reservoirs, such as virus adhering to the surfaces of follicular dendritic cells and B cells, may be hindering viral eradication. We propose to calculate the lifetime of such reservoirs and examine means of interfering with the multivalent attachment of HIV to cell surfaces via complement and Fc receptors.