CNS Viral Dynamics and Cellular Immunity During AIDS
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Purpose
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.
| Condition |
|---|
|
HIV Infections |
| Study Type: | Observational |
| 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
| Enrollment: | 4 |
| Study Start Date: | March 2006 |
| Study Completion Date: | July 2010 |
| Primary Completion Date: | June 2009 (Final data collection date for primary outcome measure) |
| Groups/Cohorts |
|---|
|
A1
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.
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|
A2
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.
|
|
B
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.
|
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Non-Probability Sample |
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. Individuals with past ART experience must have 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.
Inclusion Criteria:
- (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 A2.
- Group A1:
- CD4+ T cell count >200 cells/mm3.
- 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/mm3.
- 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.
Exclusion Criteria:
- 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.
Contacts and Locations| United States, Tennessee | |
| Vanderbilt AIDS Clinical Trials Center | |
| Nashville, Tennessee, United States, 37232-2582 | |
| Principal Investigator: | David W. Haas, MD | Vanderbilt University |
More Information
No publications provided
| Responsible Party: | David W. Haas, MD, Vanderbilt University |
| ClinicalTrials.gov Identifier: | NCT00583167 History of Changes |
| Other Study ID Numbers: | 050001, R01 MH071205 |
| Study First Received: | December 26, 2007 |
| Last Updated: | July 29, 2010 |
| Health Authority: | United States: Institutional Review Board United States: Federal Government |
Keywords provided by Vanderbilt University:
|
HIV AIDS CNS brain affects |
Additional relevant MeSH terms:
|
HIV Infections Acquired Immunodeficiency Syndrome Lentivirus Infections Retroviridae Infections RNA Virus Infections Virus Diseases |
Sexually Transmitted Diseases, Viral Sexually Transmitted Diseases Immunologic Deficiency Syndromes Immune System Diseases Slow Virus Diseases |
ClinicalTrials.gov processed this record on March 05, 2013
