International Studies Of Acquired Immune Deficiency Syndrome (AIDS)

获得性免疫缺陷综合症（艾滋病）的国际研究

• 批准号: 8336044
• 负责人: Thomas Quinn
• 金额: $ 88.8万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8336044
• 关键词: Acquired Immunodeficiency Syndrome; Acyclovir; Africa; Anti-Retroviral Agents; Asia; Bacterial Vaginosis; Behavioral; Biological; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Density; Clinical; Cohort Studies; Collaborations; Communities; Country; Dendritic Cells; Detection; Developing Countries; Disease; Disease Progression; Epidemic; Epidemiology; Failure; Female; Frequencies; Future; Genital system; Genotype; HIV; HIV-1; HPV-High Risk; Heterosexuals; Human Herpesvirus 2; Human Papillomavirus; Human papilloma virus infection; Immunologics; Incidence; Individual; Infection; Institutes; International; Intervention; Kinetics; Knowledge; Laboratories; Latin America; Life; Male Circumcision; Methods; Molecular; Monitor; Pharmaceutical Preparations; Population; Prevalence; Protocols documentation; Randomized Clinical Trials; Reporting; Risk; Sampling; Serological; Sexual Transmission; Simplexvirus; Spouses; Subgroup; T-Lymphocyte; Testing; Tissues; Trichomonas Infections; Uganda; Ulcer; Vaccines; Variant; Viral; Viral Genome; Virus Diseases; Wife; arm; base; clinically relevant; cohort; density; design; follow-up; men; microbicide; next generation; novel; pandemic disease; penis foreskin; prevent; response; superinfection; transmission process; trend

HIV/AIDS is a global pandemic with nearly 33 million individuals living with HIV infection worldwide. The objectives of this project are to define the unique epidemiological, clinical, virologic, and immunologic features of HIV infection in developing countries, to determine the viral kinetics associated with sexual transmission, and to characterize the molecular strains of HIV internationally for infectiousness and progression of disease. We previously reported the results of a randomized clinical trial of circumcision to prevent HIV acquisition among 4,996 men in Uganda. The estimated efficacy of circumcision was 51% after 2 years but has risen to nearly 68% four years later. Circumcision also afforded a decrease in acquisition of high-risk- human papillomavirus (HR-HPV) in both HIV negative circumcised men as well as the female partners of circumcised men. HR-HPV incidence was 19.7/100py in the circumcised men and 29.4/100py in the control arm (p = 0.006). The incidence of multiple of HR-HPV infections was also reduced to 6.7/100py in the circumcised men and 14.8/100py in the control arm. HR-HPV incidence was lower in the circumcised men for all genotypes and demographic/behavioral subgroups. We also assessed the efficacy of circumcision to reduce HR-HPV in female partners. At two years of follow-up female HR-HPV prevalence was 27.8% in the intervention and 38.7% in the control arm (p=0.001). HR-HPV incidence was 20.7% in the intervention arm and 26.9% in the control arm wives (p=0.008). In summary male circumcision reduces acquisition of HIV, HSV and HPV infections in men, and reduces genital ulcer disease, HR-HPV, trichomoniasis, and bacterial vaginosis in their female partners. Since male circumcision reduces HIV, HPV and HSV-2 acquisition, we examined the cellular basis for these associations and estimated the immunologic cellular densities in foreskin tissues of men who were circumcised in the trial. CD1A+ dendritic cell densities did not vary by HIV or HSV-2 serologic status. When compared to HIV-/HSV-2- men, CD4+ T-cell densities in the foreskin tissue were similar in the HIV+/HSV-2+ group, significantly decreased in the HIV+/HSV-2 - group and increased in the HIV-/HSV-2+ group. CD8+ densities were higher in the HIV+/HSV-2+ infected group compared to the HIV-/HSV-2- group and the HIV+/HSV-2- group and the HIV-/HSV-2+ group (p < 0.005). The increased CD4+ cellular density in the HIV-/HSV-2+ men may help explain why HSV-2 infected men are at increased risk for HIV acquisition. The absence of this increase in the HIV+/HSV-2+ group is likely in part due to the progressive loss of CD4+ in HIV infection. Conversely, co-infection with HIV and HSV-2 appear to synergistically increase the CD8+ T-cell densities and may partially explain the failure of acyclovir in decreasing sexual transmission of HIV in dually infected individuals. HIV superinfection has been described in a number of populations but its frequency and its clinical relevance remains unknown. We designed and tested a next generation sequencing protocol to identify HIV superinfection by targeting two regions of the HIV viral genome, p24 and gp41. The method was validated by mixing control samples infected with HIV subtypes A or D at different ratios to determine the inter- and intra-subtype sensitivity. This amplicon-based protocol was able to consistently identify distinct inter-subtype strains at ratios of 1%, and intra-subtype variants at 5%. Using stored samples from the Rakai Community Cohort Study (RCCS) in Uganda, eleven individuals who were HIV-seroconcordant but virally unlinked from their spouses were then tested with this method to detect superinfection between 2002-2005. Two female cases of HIV inter-subtype superinfection (18.2%) were identified. Our results indicate that NGS can be used for detection of HIV superinfection within large cohorts, which could assist in determining the incidence and the epidemiologic, virologic, and immunological correlates of this phenomenon. The significance of these studies is that they provide important epidemiologic, clinical, virologic and immunologic knowledge of HIV infection in developing countries, which can be utilized for monitoring future trends of the epidemic and developing behavioral and biological interventions to prevent further transmission.

HIV/艾滋病是一种全球性流行病，全世界有近 3300 万艾滋病毒感染者。该项目的目标是确定发展中国家艾滋病毒感染的独特流行病学、临床、病毒学和免疫学特征，确定与性传播相关的病毒动力学，并描述国际艾滋病毒分子毒株的传染性和进展情况。疾病。我们之前报道了乌干达 4,996 名男性进行包皮环切术预防艾滋病毒感染的随机临床试验的结果。包皮环切术的估计疗效在 2 年后为 51%，但四年后已升至近 68%。包皮环切术还可以减少 HIV 阴性的割包皮男性以及割包皮男性的女性伴侣感染高危人乳头瘤病毒 (HR-HPV) 的机会。接受包皮环切术的男性中 HR-HPV 发病率为 19.7/100py，对照组为 29.4/100py（p = 0.006）。接受包皮环切术的男性中，HR-HPV 多重感染的发生率也降低至 6.7/100py，而对照组则降低至 14.8/100py。对于所有基因型和人口/行为亚组，接受包皮环切的男性的 HR-HPV 发病率均较低。我们还评估了包皮环切术减少女性伴侣 HR-HPV 的功效。两年随访时，干预组女性 HR-HPV 患病率为 27.8%，对照组为 38.7% (p=0.001)。 干预组的 HR-HPV 发病率为 20.7%，对照组的妻子为 26.9%（p=0.008）。总之，男性包皮环切术可减少男性艾滋病毒、单纯疱疹病毒和HPV感染，并减少女性伴侣的生殖器溃疡病、HR-HPV、滴虫病和细菌性阴道病。 由于男性包皮环切术减少了 HIV、HPV 和 HSV-2 的感染，我们检查了这些关联的细胞基础，并估计了试验中接受包皮环切术的男性包皮组织中的免疫细胞密度。 CD1A+树突状细胞密度不随HIV或HSV-2血清学状态而变化。与 HIV-/HSV-2- 男性相比，HIV+/HSV-2+ 组包皮组织中的 CD4+ T 细胞密度相似，HIV+/HSV-2- 组显着降低，HIV-- 组包皮组织中 CD4+ T 细胞密度增加。 /HSV-2+组。与 HIV-/HSV-2- 组以及 HIV+/HSV-2- 组和 HIV-/HSV-2+ 组相比，HIV+/HSV-2+ 感染组的 CD8+ 密度较高 (p < 0.005)。 HIV-/HSV-2+ 男性中 CD4+ 细胞密度的增加可能有助于解释为什么 HSV-2 感染男性感染 HIV 的风险增加。 HIV+/HSV-2+ 组中没有这种增加可能部分是由于 HIV 感染中 CD4+ 逐渐丧失。相反，HIV 和 HSV-2 的共同感染似乎可以协同增加 CD8+ T 细胞密度，这可能部分解释了阿昔洛韦在减少双重感染个体中 HIV 性传播方面的失败。 HIV重复感染已在许多人群中得到描述，但其发生频率及其临床相关性仍不清楚。我们设计并测试了下一代测序方案，通过针对 HIV 病毒基因组的两个区域 p24 和 gp41 来识别 HIV 重复感染。 该方法通过以不同比例混合感染 HIV A 或 D 亚型的对照样本来确定亚型间和亚型内敏感性进行验证。这种基于扩增子的方案能够以 1% 的比率一致地识别不同的亚型间菌株，以 5% 的比率识别亚型内变异。 使用乌干达 Rakai 社区队列研究 (RCCS) 储存的样本，对 11 名 HIV 血清一致但与其配偶没有病毒关联的个体进行了测试，以检测 2002 年至 2005 年间的重复感染。 确定了两例 HIV 亚型间重复感染女性病例（18.2%）。我们的结果表明，NGS 可用于检测大型人群中的 HIV 重复感染，这有助于确定这种现象的发病率以及流行病学、病毒学和免疫学相关性。 这些研究的意义在于，它们提供了发展中国家艾滋病毒感染的重要流行病学、临床、病毒学和免疫学知识，可用于监测该流行病的未来趋势，并制定行为和生物干预措施以防止进一步传播。