MODELING CELLULAR IMMUNITY DURING HIV AND TB INFECTIONS

本提案的目的是解释TH 1型和TH 2型的作用， 人类病原体疾病进展中的型细胞因子谱 免疫缺陷病毒1型（HIV-1）和结核分枝杆菌。 我们研究了以下假设：（1）疾病的进展 在HIV感染的发病过程中， TH 1和TH 2型细胞因子的转移，这些细胞因子在细胞周期中表达。 疾病的演变。 这种范式可以预测， 以TH 2型细胞因子为特征的表型存在于终末期 疾病(2)感染潜伏期的建立和维持 结核分枝杆菌感染的可能性可以根据细胞因子 轮廓，平衡组织损伤响应与分辨率。 的 三个具体的目标是制定数学模型的基础上 在对疾病的细胞免疫应答中的复杂细胞因子网络： (1)确定TH 1/TH 2细胞因子平衡在 区分分枝杆菌感染的疾病结局 结核 具体来说，我们将调查为什么大多数人 发展为潜伏性结核感染，但其他人通过以下途径发展为疾病： 快速或缓慢的进展。(2)探讨长期TH 1/TH 2的作用 HIV-1疾病进展期间表达的细胞因子变化 确定TH 1/TH 2细胞因子失衡的预测作用， 进展(3)研究使用细胞因子作为治疗 作为免疫治疗剂的策略，单独或联合 化疗，对于潜伏性和进行性疾病， 耐药和药物敏感的HIV-1和M.结核这些 研究结果还有望使人们更好地了解共同 感染HIV-1和结核病。 将建立数学模型 反映了不同疾病的动态变化 states. 这些模型包括实验数据，并将进行分析 用数学方法表征非线性动力学 系统.多种因素的相互作用控制，激活或 促进对病原体的细胞免疫反应， 定义了 将确定支配这些相互作用的关键参数 通过数学敏感性分析。 这些结果将 结合已知的临床和实验， 数据

The goal of this proposal is to explain the role of TH1-type and TH2- type cytokine profiles in disease progression for the pathogens human immunodeficiency virus type 1 (HIV-1) and Mycobacterium tuberculosis. We investigate the following hypotheses: (1) The progression of disease during the pathogenesis of HIV infection is dependent upon a long-term shift of TH1- and TH2-type cytokines that are expressed during the evolution of the disease. This paradigm would predict that a dominant phenotype characterized by TH2-type cytokines is present in end-stage disease. (2) The establishment and maintenance of latency in infection with Mycobacterium tuberculosis may be predicted based on the cytokine profiles, balancing the tissue damaging response with resolution. The three specific aims are to formulate mathematical models based on the complex cytokine network in the cellular immune response to disease to: (1) Determine the predictive role of a TH1/TH2 cytokine balance in differentiating the disease outcomes in infection with Mycobacterium tuberculosis. Specifically, we will investigate why most individuals develop latent TB infection, yet others progress to disease, via either a fast or slow progression. (2) Explore the role of a long-term TH1/TH2 cytokine shift expressed during HIV-1 disease progression and to determine the predictive role of a TH1/TH2 cytokine imbalance in that progression. (3) Investigate the use of cytokines as therapeutic strategies as agents of immunotherapy, either alone or in conjunction with chemotherapy, for both latent and progressive disease for both drug-resistant and drug-sensitive HIV-1 and M. tuberculosis. These results are also expected to lead to a greater understanding of co- infections with HIV-1 and TB. Mathematical models will be developed that reflect the dynamics of the different diseases as well as disease states. These models include experimental data and will be analyzed using mathematical approaches for characterizing nonlinear dynamical systems. The interaction of multiple factors that control, activate or facilitate the cellular-immune response to the pathogens will be defined. Key parameters governing these interactions will be identified through mathematical sensitivity analyses. These results will incorporate, and be tested against, known clinical and experimental data.