Influence of Sex Steroids on HIV-1 Chemokine Coreceptor Expression in Women

性类固醇对女性 HIV-1 趋化因子辅助受体表达的影响

• 批准号: 7933669
• 负责人: Amie L Meditz
• 金额: $ 13.22万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7933669
• 关键词: Age; Aging; Agonist; Biology; Biology of HIV Transmission; CCL3 gene; CCL3L1 gene; CCL4 gene; CCR5 gene; CD4 Positive T Lymphocytes; CXCL12 gene; CXCR4 gene; Caring; Cervical; Data; Development; Disease Progression; Enzyme-Linked Immunosorbent Assay; Estrogens; Female; Genital system; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; HIV; HIV-1; Individual; Infection; Irrigation; Knowledge; Laboratories; Life; Ligands; Link; Measures; Medical; Menopause; Messenger RNA; Peripheral Blood Mononuclear Cell; Physiological; Placebos; Plasma; Postmenopause; Predisposition; Principal Investigator; Production; Progesterone; RANTES; Randomized; Relative (related person); Replacement Therapy; Report (account); Research; Specimen; Staging; Viral Load result; Whole Blood; Woman; age related; chemokine; chemokine receptor; cohort; density; hormone therapy; in vivo; insight; mRNA Expression; peripheral blood; receptor; receptor density; reproductive

DESCRIPTION (provided by applicant): Women constitute nearly half of the 33 million HIV-1-infected individuals in the world and the vast majority acquire this infection heterosexually. Multiple lines of evidence suggest that female sex hormones alter susceptibility of HIV-1 (HIV) as well as disease progression, but mechanisms underlying this are unknown. Expression of the HIV coreceptor, CCR5, and its ligands, the p-chemokines, has been strongly linked to HIV susceptibility and disease progression, however their relative importance in vivo is controversial. Preliminary data from our and other laboratories suggest that estrogen (E) and progesterone (P) alter expression of CCR5 and its ligands in whole blood (WB) and the female genital tract. Specifically, E upregulates CCR5 and its ligands, whereas P downregulates them. We hypothesize that both E and P modulate CCR5 and one of its most important and abundant ligands, CCL5, but changes in CCL5 predominate. In the proposed studies, the influence of E and P on HIV coreceptors and their ligands will be determined by studying three cohorts of women before and after hormonal therapy: reproductive-age women who undergo gonadotrophin- releasing hormone agonist-induced sex hormone suppression randomized to E or placebo for 3 months then P for 2 weeks in the third month; postmenopausal women randomized to E or placebo for 4 weeks followed by E+P for 12 days; and HIV seropositive postmenopausal women who receive E for 4 weeks followed by E+P for 12 days. CCR5 and CXCR4 density will be determined by flow cytometric analysis of whole blood and cervical CD4+ T cells; inducible and constitutive p-chemokine and CXCL12 production will be measured in whole blood and cervical lavage specimens by ELISA; PBMC CCR5, CXCR4, and CCL5 mRNA will be determined by RT PCR; and, in HIV seropositive women, plasma and genital tract viral load will be measured. Knowledge of the influence of physiologic levels of E, P and aging on HIV chemokine coreceptors, their ligands, and genital tract viral load could provide mechanistic insight into the biology of HIV transmission and disease progression in women. Ultimately, this information is needed to develop rational standard practices of prescribing hormonal therapies to HIV infected women at all stages of life. RELEVANCE: Research has suggested that sex hormones may alter a woman's susceptibility to HIV. A receptor called CCR5 is required for HIV to infect CD4+ T cells and may be regulated by female sex hormones. This study will evaluate the influence of female sex hormones and aging on HIV biology, information critically needed to provide rational medical care for women at all stages of life.

描述（由申请人提供）：妇女构成了世界上3300万HIV-1感染者中的几乎一半，而绝大多数人则以异性获得这种感染。多种证据表明，女性性激素改变了HIV-1（HIV）和疾病进展的敏感性，但是这是尚不清楚的机制。 HIV共肽CCR5及其配体的表达与HIV易感性和疾病进展密切相关，但是它们在体内的相对重要性是有争议的。来自我们和其他实验室的初步数据表明，雌激素（E）和孕酮（P）在全血（WB）和女性生殖道中改变CCR5及其配体的表达。具体而言，E上调CCR5及其配体，而P下调了CCR5。我们假设E和P均调节CCR5及其最重要，最丰富的配体CCL5之一，但CCL5的变化占主导地位。在拟议的研究中，E和P对HIV共受体及其配体的影响将通过研究激素治疗前后的三个妇女来确定：生殖时代的妇女，这些妇女的雌性妇女释放了激素激素激素激素激素激素诱导的性激素诱导的性激素随机抑制了E或将E抑制为E或地位3个月，然后在第三个月中为第三个月份per per per per per per per。绝经后妇女随机分配到E或安慰剂4周，然后进行E+P 12天；和HIV血清阳性的绝经后妇女接受E 4周，然后接受E+P 12天。 CCR5和CXCR4密度将通过全血流式细胞术分析和宫颈CD4+ T细胞来确定； ELISA将在全血和宫颈灌洗样本中测量诱导和构成型p-化学因子和CXCL12的产生。 PBMC CCR5，CXCR4和CCL5 mRNA将由RT PCR确定；并且，将测量HIV血清阳性女性，血浆和生殖道病毒载量。了解E，P和衰老对HIV趋化因子共肽的影响，其配体以及生殖道病毒载量的知识可以提供对女性HIV传播和疾病进展的生物学的机械洞察力。最终，需要此信息来开发为在生活的各个阶段为艾滋病毒感染的妇女开出荷尔蒙疗法的理性标准实践。 相关性：研究表明，性激素可能会改变女性对艾滋病毒的敏感性。 HIV需要一种称为CCR5的受体才能感染CD4+ T细胞，并且可能受女性性激素调节。这项研究将评估女性性激素和衰老对艾滋病毒生物学的影响，这是在生活的各个阶段为妇女提供合理的医疗服务所需的信息。