Mechanism/predictors of genital/rectal HIV shedding during ART w/plasma <50c/mL

血浆 <50c/mL 的 ART 期间生殖器/直肠 HIV 脱落的机制/预测因素

• 批准号: 7898365
• 负责人: Lisa M Frenkel
• 金额: $ 34.59万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7898365
• 关键词: Adherence; Adult; Anal Sex; Anatomic Sites; Anti-Retroviral Agents; Antiviral Agents; Archives; Biological Assay; Biopsy; Blood; CD4 Positive T Lymphocytes; Cells; Cervical; Clinical; Communities; DNA; Detection; Development; Disease; Drug resistance; Environment; Enzyme Immunoassay; Epidemiologic Factors; Epidemiological Factors; Evolution; Failure; Frequencies; Genetic; Genital system; Genome; Goals; HIV; HIV-1; IL8 gene; Immune; Individual; Infection; Inflammation; Inflammatory; Interleukin-6; Language; Lead; Liquid Chromatography; Longitudinal Studies; Lymphocyte; Mutation; Pathogenesis; Penetration; Peru; Pharmaceutical Preparations; Pharmacotherapy; Phylogenetic Analysis; Plasma; Process; Proctitis; Production; Proviruses; Public Health; RNA; Rectum; Relative (related person); Research Personnel; Reverse Transcription; Risk; Risk Factors; Seminal Plasma; Sex Behavior; Sexual Partners; Sexual Transmission; Simplexvirus; Specimen; Testing; Time; Time Study; Tissues; Transcriptional Activation; Transudate; Trauma; Treatment Failure; Variant; Viral; Viral Load result; Virus; Virus Replication; Virus Shedding; Woman; Work; antiretroviral therapy; cytokine; drug resistant virus; effective therapy; genital secretion; high risk; insight; latent virus activation; men; mutant; non-nucleoside reverse transcriptase inhibitors; particle; peripheral blood; pill; prevent; programs; rectal; tool; transmission process; treatment strategy; virus genetics

In Peru antiretroviral therapy (ART) will be broadly available to HIV-1 infected individuals with <250 CD4 cells/uL. We hypothesize that: 1. A subset of Peruvian adults who initiate ART will have discordant suppression of viral replication in the blood and genital tract/rectum. 2. Continued shedding of virus from the genital tract or rectum will often be due to virus production following immune activation of latently infected cells, which will occur without the development of drug resistance; however, in some instances shedding will be due to continued viral replication, which will be associated with selection of drug-resistant virus. Discerning the relative frequency of genital/rectal shedding by these mechanisms is important for public health. While shedding without replication could place sexual partners at risk of infection, we suspect the infectiousness of these shedders will be low due to shedding of virus at low viral loads. In contrast, those that shed genital/rectal virus in association with viral replication will likely shed higher levels of virus, and have a higher risk of shedding drug-resistant virus. These latter individuals would present a higher public health risk, as they would be more likely to transmit virus due to higher genital/rectal viral loads and would be more likely to transmit drug-resistant virus, diminishing the benefits of ART within the community. By studies of blood and genital/rectal secretions and biopsies, including viral loads and genetics over time, this study aims to determine the rate of discordant shedding of virus in the blood plasma and genital tract/rectal; determine the epidemiological factors associated with discordant shedding; and provide further insight into the pathogenesis of expression of virus from activation of latent provirus versus full-cycles of replication with selection of drug-resistant virus. Lay language description of relevance to public health: Viral shedding from the rectum and genital tract allows transmission of HIV. Effective treatment that suppresses viral replication in the blood, does not curtail rectal and genital tract viral shedding from about one-third of treated individuals. By studying viral genetics we aim to discern the mechanisms that allow HIV to be shed from the genital tract and rectum when suppressed in the blood. A better understanding of this discordant genital tract and rectal shedding should allow us to develop better treatment strategies that should reduce HIV transmission.

在秘鲁，CD4<250 的 HIV-1 感染者将广泛获得抗逆转录病毒治疗 (ART) 细胞/uL。我们假设： 1. 一部分开始 ART 的秘鲁成年人会出现不一致的情况 抑制血液和生殖道/直肠中的病毒复制。 2. 病毒持续散发 生殖道或直肠通常是由于潜在感染者的免疫激活后产生病毒所致 细胞，这种情况会在不产生耐药性的情况下发生；然而，在某些情况下，脱落会 是由于病毒的持续复制，这将与耐药病毒的选择有关。 通过这些机制辨别生殖器/直肠脱落的相对频率对于公众来说很重要 健康。虽然未经复制的脱落可能会使性伴侣面临感染的风险，但我们怀疑 由于病毒载量较低，这些传播者的传染性较低。相比之下，那些 与病毒复制相关的生殖器/直肠病毒的脱落可能会脱落更高水平的病毒，并且具有 产生耐药病毒的风险更高。后者将带来更高的公共健康风险， 因为由于生殖器/直肠病毒载量较高，他们更有可能传播病毒，并且更有可能 传播耐药病毒，削弱抗逆转录病毒治疗在社区内的益处。通过血液研究 以及生殖器/直肠分泌物和活检，包括随时间变化的病毒载量和遗传学，本研究旨在 确定血浆和生殖道/直肠中病毒的不一致脱落率；确定 与不一致排泄相关的流行病学因素；并提供进一步的见解 潜伏原病毒激活与全复制周期的病毒表达发病机制 耐药病毒的选择。 与公共卫生相关的通俗语言描述：直肠和生殖道的病毒脱落 允许传播艾滋病毒。抑制血液中病毒复制的有效治疗不会减少 约三分之一的接受治疗的个体出现直肠和生殖道病毒脱落。通过研究病毒遗传学 我们的目标是找出艾滋病毒从生殖道和直肠排出的机制 被压抑在血液之中。更好地了解这种不和谐的生殖道和直肠脱落应该 使我们能够制定更好的治疗策略，减少艾滋病毒的传播。