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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，但他们往往需要治疗合并症。我们的长期目标是改善艾滋病毒感染者的生活合并癌症，这是cART时代死亡的主要原因。HIV感染者合并症与未感染艾滋病毒的患者相比，癌症患者因癌症而死亡的风险更高。几研究表明，无效（非抑制性）cART与对癌症化疗（CHEMO）和死亡率。确定控制有效性的因素，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。我们推断 CHEMO可以调节cART的抗病毒活性，这是基于观察到抑制细胞增殖，胸苷酸合成酶（TS）是CHEMO的主要靶点，其改变细胞内各种个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）可对cART产生抑制和增强作用，影响HIV的发展耐药性和体内HIV储存库。在初步研究中，吉西他滨（GCB）增强了抗HIV NRTI TFV、ABC和FTC在原代细胞中的活性。相比之下，培美曲塞（PTX）可抑制FTC， 3 TC活动机制研究表明，PTX降低了FTCtp的浓度，竞争性内源核苷酸（dCTP），其是原代细胞中FTC功效的决定因素。一致根据这些数据，TFV/FTC/度鲁特韦组合在不存在的情况下抑制HIV，但在不存在的情况下不抑制HIV。存在，PTX。这些数据表明，接受某些cART/TSi治疗的HIV感染患者联合用药实际上可能只有2种而不是3种活性ART，降低了cART的总体效力，增加了耐药性的风险，扩大了艾滋病毒的储存库。人源化小鼠的初步研究证明GCB可使TFV对血浆HIV RNA的抑制作用增强6 log 10单位，而PTX 取消FTC活动。这些数据是第一个证据表明，基于TSi的CHEMO可以有反对影响体内cART疗效，影响HIV控制，从而产生病毒耐药性和水库的大小。该提案将评估PTX、GCB和其他批准的TSi对 cART疗效。有三个具体目标。具体目标1：评价和表征TS的作用抑制剂（TSi）对NRTI在体外和人源化小鼠中的原代CD 4 + T细胞中的抗HIV活性的影响。具体目的2：评价cART/TSi组合对静息CD 4 T细胞HIV储库的影响。具体目标3：评价cART/TSi的持久性（缺乏HIV耐药性出现）和毒性在长期治疗HIV感染的过程中。目前还没有治疗指南，在HIV感染的癌症患者中使用cART和CHEMO，但这一建议可能有助于描述减少艾滋病患者的癌症死亡。

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.