CNS Viral Dynamics and Cellular Immunity During AIDS
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.
|Study Design:||Observational Model: Cohort
Time Perspective: Prospective
|Official Title:||CNS Viral Dynamics and Cellular Immunity During AIDS|
- 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. [ Time Frame: end of study ] [ Designated as safety issue: No ]
- To measure intrathecal and systemic cellular immune responses against HIV-1 and to assess how these responses relate to intrathecal viral replication. [ Time Frame: end of study ] [ Designated as safety issue: No ]
- To correlate intrathecal viral replication and anti-HIV CTL responses with the degree of glial activation/proliferation and neuronal dropout in the brain. [ Time Frame: end of study ] [ Designated as safety issue: No ]
Biospecimen Retention: Samples With DNA
whole blood, plasma, CSF
|Study Start Date:||March 2006|
|Study Completion Date:||July 2010|
|Primary Completion Date:||June 2009 (Final data collection date for primary outcome measure)|
HIV-infected subjects who are at least 18 years of age, with no ART in the previous 3 months, and with plasma HIV-1 RNA >20,000 copies/mL. CD4+ T cell count >200 cells/mm3. Group A1 will undergo continuous CSF sampling via intrathecal catheter.
HIV-infected subjects who are at least 18 years of age, with no ART in the previous 3 months, and with plasma HIV-1 RNA >20,000 copies/mL. CD4+ T cell count <200 cells/mm3. Group A2 will undergo continuous CSF sampling via intrathecal catheter.
HIV-infected subjects who are at least 18 years of age, with no ART in the previous 3 months, and with plasma HIV-1 RNA >20,000 copies/mL. Group B will not undergo continuous CSF sampling, but will undergo sparse CSF sampling by lumbar punctures.
|United States, Tennessee|
|Vanderbilt AIDS Clinical Trials Center|
|Nashville, Tennessee, United States, 37232-2582|
|Principal Investigator:||David W. Haas, MD||Vanderbilt University|