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:
- 金额:$ 33.73万
- 依托单位:
- 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:
- 关键词:AffectBiological AssayBloodBlood Chemical AnalysisCD4 Positive T LymphocytesCancer EtiologyCancer PatientCause of DeathCellsCessation of lifeChemotherapy-Oncologic ProcedureClinicalDNADataDevelopmentDrug CombinationsDrug resistanceEffectivenessFeedbackGenotypeGoalsGuidelinesHIVHIV InfectionsHIV resistanceHistopathologyIn VitroLamivudineLicensingMalignant NeoplasmsMalignant neoplasm of lungMeasuresMonitorNucleotide BiosynthesisNucleotidesPatientsPemetrexedPenetrationPharmaceutical PreparationsPlasmaPopulationPurinesPyrimidinesRNARegimenRegulatory T-LymphocyteResearchResistanceRestRiskSafetyTenofovirThymidylate SynthaseThymidylate Synthase InhibitorTissuesToxic effectTreatment EfficacyVertebral columnViralViral PhysiologyViremiaVirusVirus Replicationabacavirantiretroviral therapychemotherapycomorbidityemtricitabineenzyme biosynthesisgemcitabinehigh riskhumanized mouseimmune checkpointimprovedin vivomortalityresponsetherapy outcometreatment guidelinesviral 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.
项目总结
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:
- 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.
- DOI:10.24875/aidsrev.22000013
- 发表时间:2022-10-25
- 期刊:
- 影响因子:2.2
- 作者:Fraker, Sally;Atkinson, Benjamin;Heredia, Alonso
- 通讯作者:Heredia, Alonso
Human Hematopoietic Stem Cell (HSC)-Engrafted NSG Mice for HIV Latency Research.
- DOI:10.1007/978-1-0716-1871-4_17
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Alonso Heredia其他文献
Alonso Heredia的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Alonso Heredia', 18)}}的其他基金
Image-guided intra-arterial administration of antibody-releasing glial progenitors to control the HIV CNS reservoir.
图像引导动脉内注射抗体释放神经胶质祖细胞来控制 HIV 中枢神经系统储库。
- 批准号:
10512770 - 财政年份:2022
- 资助金额:
$ 33.73万 - 项目类别:
Image-guided intra-arterial administration of antibody-releasing glial progenitors to control the HIV CNS reservoir.
图像引导动脉内注射抗体释放神经胶质祖细胞来控制 HIV 中枢神经系统储库。
- 批准号:
10684314 - 财政年份:2022
- 资助金额:
$ 33.73万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 33.73万 - 项目类别:
Long-Term Inhibition of HIV transcription by targeting cellular CDK9 in vivo.
通过体内靶向细胞 CDK9 长期抑制 HIV 转录。
- 批准号:
8788234 - 财政年份:2014
- 资助金额:
$ 33.73万 - 项目类别:
Long-Term Inhibition of HIV transcription by targeting cellular CDK9 in vivo.
通过体内靶向细胞 CDK9 长期抑制 HIV 转录。
- 批准号:
8847280 - 财政年份:2014
- 资助金额:
$ 33.73万 - 项目类别:
Control of HIV drug resistance in older patients
老年患者艾滋病毒耐药性的控制
- 批准号:
7753133 - 财政年份:2009
- 资助金额:
$ 33.73万 - 项目类别:
Control of HIV drug resistance in older patients
老年患者艾滋病毒耐药性的控制
- 批准号:
7897760 - 财政年份:2009
- 资助金额:
$ 33.73万 - 项目类别:
相似海外基金
Establishment of a new biological assay using Hydra nematocyst deployment
利用水螅刺丝囊部署建立新的生物测定方法
- 批准号:
520728-2017 - 财政年份:2017
- 资助金额:
$ 33.73万 - 项目类别:
University Undergraduate Student Research Awards
POINT-OF-CARE BIOLOGICAL ASSAY FOR DETERMINING TISSUE-SPECIFIC ABSORBED IONIZING RADIATION DOSE (BIODOSIMETER) AFTER RADIOLOGICAL AND NUCLEAR EVENTS.
用于确定放射和核事件后组织特异性吸收电离辐射剂量(生物剂量计)的护理点生物测定。
- 批准号:
10368760 - 财政年份:2017
- 资助金额:
$ 33.73万 - 项目类别:
POINT-OF-CARE BIOLOGICAL ASSAY FOR DETERMINING TISSUE-SPECIFIC ABSORBED IONIZING RADIATION DOSE (BIODOSIMETER) AFTER RADIOLOGICAL AND NUCLEAR EVENTS.
用于确定放射和核事件后组织特异性吸收电离辐射剂量(生物剂量计)的护理点生物测定。
- 批准号:
10669539 - 财政年份:2017
- 资助金额:
$ 33.73万 - 项目类别:
POINT-OF-CARE BIOLOGICAL ASSAY FOR DETERMINING TISSUE-SPECIFIC ABSORBED IONIZING RADIATION DOSE (BIODOSIMETER) AFTER RADIOLOGICAL AND NUCLEAR EVENTS.
用于确定放射和核事件后组织特异性吸收电离辐射剂量(生物剂量计)的护理点生物测定。
- 批准号:
9570142 - 财政年份:2017
- 资助金额:
$ 33.73万 - 项目类别:
POINT-OF-CARE BIOLOGICAL ASSAY FOR DETERMINING TISSUE-SPECIFIC ABSORBED IONIZING RADIATION DOSE (BIODOSIMETER) AFTER RADIOLOGICAL AND NUCLEAR EVENTS.
用于确定放射和核事件后组织特异性吸收电离辐射剂量(生物剂量计)的护理点生物测定。
- 批准号:
9915803 - 财政年份:2017
- 资助金额:
$ 33.73万 - 项目类别:
COVID-19 Supplemental work: POINT-OF-CARE BIOLOGICAL ASSAY FOR DETERMINING TISSUE-SPECIFIC ABSORBED IONIZING RADIATION DOSE (BIODOSIMETER).
COVID-19 补充工作:用于确定组织特异性吸收电离辐射剂量的护理点生物测定(生物剂量计)。
- 批准号:
10259999 - 财政年份:2017
- 资助金额:
$ 33.73万 - 项目类别:
Drug discovery based on a new biological assay system using Yeast knock-out strain collection
基于使用酵母敲除菌株收集的新生物测定系统的药物发现
- 批准号:
21580130 - 财政年份:2009
- 资助金额:
$ 33.73万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Machine learning for automatic gene annotation using high-throughput biological assay data
使用高通量生物测定数据进行自动基因注释的机器学习
- 批准号:
300985-2004 - 财政年份:2005
- 资助金额:
$ 33.73万 - 项目类别:
Postdoctoral Fellowships
Machine learning for automatic gene annotation using high-throughput biological assay data
使用高通量生物测定数据进行自动基因注释的机器学习
- 批准号:
300985-2004 - 财政年份:2004
- 资助金额:
$ 33.73万 - 项目类别:
Postdoctoral Fellowships