CNS Viral Dynamics and Cellular Immunity During AIDS
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 4
- 试验地点
- 1
- 主要终点
- To characterize intrathecal viral replication during chronic untreated HIV-1 infection, and to assess how intrathecal viral replication relates to stage of HIV-1 disease.
研究概览
简要总结
Understanding whether or not viral replication occurs in the brain during chronic untreated HIV-1 infection is of undeniable importance, and has implications for treatment and research priorities. Evidence suggests that viral replication in the CNS occurs at the extremes of HIV-1 disease. Brain involvement has been reported during acute infection, and there is convincing evidence of CNS viral replication during HIV-associated dementia (HAD) and advanced AIDS. Some human and primate data suggest that viral RNA and proteins may be absent from brains of some individuals with chronic untreated HIV-1 infection despite abundant proviral DNA. However, the extent of viral replication in the brain is not known for most of the 42 million people worldwide living with untreated HIV-1 infection.
Why is viral replication in the brain such a pivotal issue? Microglial cells and macrophages are primary targets for intrathecal HIV-1 replication, and this can promote neuronal injury through direct effects of gp120 and tat, and indirect induction of toxic mediators. Low-grade injury over years or decades would likely be deleterious, particularly as the population ages. Because treatment guidelines allow systemic HIV-1 replication to continue until CD4+ T cell counts decline considerably, antiretroviral therapy (ART) is not recommended for many persons living with HIV. Demonstrating replication in the brain during chronic HIV-1 infection may affect treatment strategies and encourage investigation.
Identifying factors that modulate intrathecal viral replication is equally important. Anti-HIV-1 cytotoxic T lymphocytes (CTL) partially control systemic viral replication and delay disease progression. Although available data has been provocative, the role of anti-HIV CTL in the CNS has received little attention. To fill this gap we will examine relationships between intrathecal viral replication, CTL responses, and glial activation/proliferation during HIV-1 infection. These studies will be relevant not only to AIDS but to other inflammatory diseases of the CNS as well.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(All subjects in Groups A1, A2 and B):
- •At least 18 years of age.
- •No more than one month of ART in the past.
- •No ART in the previous 3 months.
- •Platelet count >100,000 cells/mm3 on most recent determination within 60 days prior to first study lumbar puncture.
- •Normal prothrombin time (PT) and partial thromboplastin time (PTT) on most recent determination within 60 days prior to first study lumbar puncture.
- •Among individuals with past ART experience, the ability to construct an ART regimen predicted to completely suppress plasma HIV-1 RNA, based on results of viral susceptibility testing that is done as a routine part of clinical practice.
- •Plasma HIV-1 RNA >20,000 copies/mL.
- •Additional Inclusion Criteria for Groups A1 and A
- •Group A1:
- •CD4+ T cell count >200 cells/mm
- •CSF HIV-1 RNA >2,000 copies/mL on screening lumbar puncture.
- •No history of significant allergy to beta lactam antibiotics, including penicillins and cephalosporins.
- •No history of allergy to vancomycin.
- •Group A2:
- •CD4+ T cell count <200 cells/mm
- •CSF HIV-1 RNA >2,000 copies/mL on screening lumbar puncture.
- •No history of significant allergy to beta lactam antibiotics, including penicillins and cephalosporins.
- •No history of allergy to vancomycin.
排除标准
- •Evidence of CNS opportunistic infections or space occupying lesion.
- •History of significant CNS disorder unrelated to HIV infection such as trauma, congenital malformations or genetic disorders.
- •History of seizures.
- •As determined by the investigator, a significant active or previous history of cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, or endocrine disease(s) that would interfere with study participation.
- •Evidence or suspicion of vascular or Alzheimer's type dementias.
- •Evidence or suspicion of Parkinson's disease.
- •History of allergy to lidocaine.
- •Implanted metal objects that make MRI contraindicated. This may require consultation with colleagues in the Vanderbilt Dept. of Radiology.
- •Women who are pregnant or breastfeeding.
- •Women with a positive pregnancy test on enrollment or prior to study drug administration.
- •Women of childbearing potential (WOCBP) who are unwilling or unable to use an adequate method of contraception to avoid pregnancy throughout the study in such a manner that the risk of pregnancy is minimized.
- •Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.
结局指标
主要结局
To characterize intrathecal viral replication during chronic untreated HIV-1 infection, and to assess how intrathecal viral replication relates to stage of HIV-1 disease.
时间窗: end of study
To correlate intrathecal viral replication and anti-HIV CTL responses with the degree of glial activation/proliferation and neuronal dropout in the brain.
时间窗: end of study
To measure intrathecal and systemic cellular immune responses against HIV-1 and to assess how these responses relate to intrathecal viral replication.
时间窗: end of study
次要结局
未报告次要终点
研究者
David Haas
Professor of Medicine
Vanderbilt University