Impact of concomitant chemotherapy on HIV resistance to cART and reservoir size

同步化疗对 HIV 对 cART 耐药性和储库大小的影响

• 批准号: 10321231
• 负责人: Alonso Heredia
• 金额: $ 33.06万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-08 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10321231
• 关键词: Affect; Biological Assay; Blood; Blood Chemical Analysis; CD4 Positive T Lymphocytes; Cancer Etiology; Cancer Patient; Cause of Death; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Clinical; DNA; Data; Development; Drug Combinations; Drug resistance; Effectiveness; Genotype; Goals; Guidelines; HIV; HIV Infections; HIV resistance; Histopathology; In Vitro; Lamivudine; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Monitor; Nucleotide Biosynthesis; Nucleotides; Outcome; Patients; Pemetrexed; Penetration; Pharmaceutical Preparations; Plasma; Population; Purines; Pyrimidines; RNA; Regimen; Regulatory T-Lymphocyte; Research; Resistance; Rest; Risk; Safety; Tenofovir; Thymidylate Synthase; Thymidylate Synthase Inhibitor; Tissues; Toxic effect; Treatment Efficacy; Vertebral column; Viral; Viremia; Virus; Virus Replication; abacavir; antiretroviral therapy; base; chemotherapy; comorbidity; emtricitabine; enzyme feedback; gemcitabine; high risk; humanized mouse; immune checkpoint; improved; in vivo; inhibitor; mortality; response; treatment guidelines; viral resistance

PROJECT SUMMARY Patients with HIV infection are living longer thanks to combination antiretroviral therapy (cART), but they often necessitate treatment for comorbidities. Our long-term goal is to improve the lives of HIV-infected patients with comorbid cancer, a main cause of mortality in the cART era. HIV-infected patients with comorbid cancer have a higher risk of dying as a result of their cancer than non-HIV-infected patients. Several studies have demonstrated an association between ineffective (non-suppressive) cART and poor response to cancer chemotherapy (CHEMO) and mortality. Identification of the factors controlling the effectiveness of cART in the context of CHEMO could reduce cancer deaths in HIV-infected patients. We reasoned that CHEMO could modulate the antiviral activity of cART, based on the observation that inhibition of cellular thymidylate synthase (TS), a main target of CHEMO, alters intracellular concentrations of various nucleotides. Our goal is to evaluate the effects of TSi on the antiviral activity of cART. Our hypothesis is that TS inhibitors (TSi) can have inhibitory and enhancing effects on cART, impacting development of HIV resistance and the HIV reservoir in vivo. In Preliminary Studies, gemcitabine (GCB) enhanced the anti-HIV activities of NRTIs TFV, ABC and FTC in primary cells. In contrast, pemetrexed (PTX) inhibited FTC and 3TC activities. Mechanistic studies showed that PTX lowered the concentrations of FTCtp relative to its competing endogenous nucleotide (dCTP), which is a determinant of FTC efficacy in primary cells. Consistent with these data, the TFV/FTC/dolutegravir combination suppressed HIV in the absence, but not in the presence, of PTX. These data suggested that HIV-infected patients treated with certain cART/TSi combinations could actually have only 2, rather than 3, active ARTs, decreasing the overall potency of cART, increasing the risk of drug resistance and expanding HIV reservoirs. Preliminary Studies in humanized mice demonstrated that GCB enhances TFV inhibition of plasma HIV RNA by up to 6 log10 units, whereas PTX abrogated FTC activity. These data are the first evidence that TSi-based CHEMO can have opposing effects on cART efficacy in vivo, impacting control of HIV and thereby development of viral resistance and size of the reservoir. This proposal will evaluate the effects of PTX, GCB and other approved TSi on cART efficacy. There are three Specific Aims. Specific Aim 1: To evaluate and characterize the effects of TS inhibitors (TSi) on the anti-HIV activities of NRTIs in primary CD4+ T cells in vitro and in humanized mice. Specific Aim 2: To evaluate the impact of cART/TSi combinations on the resting CD4 T cell HIV reservoir. Specific Aim 3: To evaluate durability (lack of HIV resistance emergence) and toxicity of cART/TSi combinations during long-term treatment of HIV infection. Currently there are no treatment guidelines for the use of cART and CHEMO in HIV-infected patients with cancer, but this proposal could help to delineate guidelines and decrease cancer deaths in patients with HIV.

项目总结 由于联合抗逆转录病毒疗法(CART)，艾滋病毒感染患者的寿命更长，但他们经常 必须对合并症进行治疗。我们的长期目标是改善艾滋病毒感染者的生活 与癌症并存，这是Cart时代死亡的主要原因。HIV感染患者的并存情况 癌症患者死于癌症的风险高于未感染艾滋病毒的患者。几个 研究表明，无效(非抑制性)CART与不良反应之间存在关联 癌症化疗(化疗)和死亡率。确定控制治疗效果的因素 在化疗的背景下，CART可以减少艾滋病毒感染患者的癌症死亡。我们推论说 化疗可以调节CART的抗病毒活性，根据观察，对细胞的抑制 胸苷酸合酶(TS)是化疗的主要靶点，它改变细胞内各种不同的浓度 核苷酸。我们的目标是评估TSI对CART抗病毒活性的影响。我们的假设是 TS抑制物(TSI)对CART具有抑制和促进作用，影响HIV的发展 体内的抗药性和艾滋病毒的储存库。在初步研究中，吉西他滨(GCB)增强了抗HIV 原代细胞中NRTIs TFV、ABC和FTC的活性。相比之下，培美曲塞(PTX)可抑制FTC和 3TC活动。机制研究表明，PTX降低FTCtp的浓度相对于其 竞争内源核苷酸(DCTP)，这是原代细胞中FTC疗效的决定因素。一致 有了这些数据，TFV/FTC/多洛替格列韦组合在缺乏情况下抑制了HIV，但在 PTX的存在。这些数据表明，艾滋病毒感染患者接受了某些CART/TSI治疗 组合实际上可能只有2个，而不是3个，活动的艺术，降低了CART的整体效力， 增加了抗药性的风险，扩大了艾滋病毒的宿主。人源化小鼠的初步研究 结果表明，GCB可增强TFV对血浆HIV RNA的抑制作用达6log10个单位，而PTX 废除了联邦贸易委员会的活动。这些数据是基于TSI的化疗可能具有相反作用的第一个证据 对体内CART效果的影响，影响艾滋病毒的控制，从而发展病毒抗药性 以及水库的大小。该提案将评估PTX、GCB和其他批准的TSI对 购物车的功效。有三个具体目标。具体目标1：评估和表征TS的效果 抑制物(TSI)在体外和人源化小鼠中对原代CD4+T细胞NRTIs抗HIV活性的影响。 具体目的2：评估CART/TSI联合治疗对静息的CD4T细胞HIV储备库的影响。 具体目标3：评估CART/TSI的持久性(缺乏对艾滋病毒的抵抗力)和毒性 在长期治疗艾滋病毒感染期间进行联合治疗。目前还没有治疗指南。 在HIV感染的癌症患者中使用CART和化疗，但这一建议可能有助于描述 指导方针和减少艾滋病毒患者的癌症死亡。