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

基本信息

批准号：
10544715
负责人：
Alonso Heredia
金额：
$ 33.73万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-08 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544715
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 Feedback Genotype Goals Guidelines HIV HIV Infections HIV resistance Histopathology In Vitro Lamivudine Licensing Malignant Neoplasms Malignant neoplasm of lung Measures Monitor Nucleotide Biosynthesis Nucleotides 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 Viral Physiology Viremia Virus Virus Replication abacavir antiretroviral therapy chemotherapy comorbidity emtricitabine enzyme biosynthesis gemcitabine high risk humanized mouse immune checkpoint improved in vivo mortality response therapy outcome treatment guidelines viral resistance

项目摘要

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.

项目摘要由于抗逆转录病毒疗法（CART），HIV感染的患者的寿命更长，但他们经常需要治疗合并症。我们的长期目标是改善感染HIV的患者的生活与合并症的癌症一起，这是购物车时代死亡率的主要原因。艾滋病毒感染患者合并症癌症因癌症而与非HIV感染患者相比，癌症死亡的风险更高。一些研究表明，无效的（无抑制）手推车与对癌症化学疗法（化学疗法）和死亡率。识别控制有效性的因素在化学疗法的背景下，推车可以减少感染HIV的患者的癌症死亡。我们认为这一点基于观察到抑制细胞胸苷酸合酶（TS）是化学疗法的主要靶标，改变各种细胞内浓度核苷酸。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抑制剂（TSI）可以对购物车具有抑制作用和增强作用，从而影响HIV的发展抗性和体内HIV储层。在初步研究中，吉西他滨（GCB）增强了抗HIV NRTIS TFV，ABC和FTC在原代细胞中的活性。相比之下，Pemetrexed（PTX）抑制了FTC和 3TC活动。机械研究表明，PTX相对于其其降低了FTCTP的浓度竞争性内源性核苷酸（DCTP），它是原代细胞中FTC功效的决定因素。持续的有了这些数据，TFV/FTC/DoluteGravir组合在不存在的情况下抑制了HIV，但在 PTX的存在。这些数据表明用某些CART/TSI治疗的HIV感染患者组合实际上只有2个，而不是3个活性艺术，从而降低了购物车的整体效力，增加耐药性和扩大HIV储藏的风险。人性化小鼠的初步研究证明GCB可增强TFV对血浆HIV RNA的抑制作用，最多6 log10单位，而PTX 废除了FTC活性。这些数据是基于TSI的化学疗法的第一个证据对体内卡车功效的影响，影响艾滋病毒的控制，从而发展病毒性和水库的大小。该建议将评估PTX，GCB和其他认可的TSI对购物车功效。有三个特定的目标。特定目的1：评估和表征TS的影响对原代CD4+ T细胞在体外和人源化小鼠中NRTI的抗HIV活性的抑制剂（TSI）。具体目标2：评估CART/TSI组合对静止CD4 T细胞HIV储量的影响。特定目的3：评估耐用性（缺乏HIV耐药性出现）和CART/TSI的毒性长期治疗HIV感染期间的组合。目前尚无针对在感染HIV的癌症患者中使用购物车和化学疗法，但该提案可以帮助描述指南和减少HIV患者的癌症死亡。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Use of Humanized Mouse Models for Studying HIV-1 Infection, Pathogenesis and Persistence.

使用人源化小鼠模型研究 HIV-1 感染、发病机制和持久性。

DOI：
发表时间：
2020
期刊：
Journal of AIDS and HIV treatment
影响因子：
0
作者：
Weichseldorfer,Matthew;Heredia,Alonso;Reitz,Marvin;Bryant,JosephL;Latinovic,OlgaS
通讯作者：
Latinovic,OlgaS

Humanized mouse models for preclinical evaluation of HIV cure strategies.