CNS (Central Nervous System) Viral Dynamics and Cellular Immunity During AIDS

NCT00583167 | Completed DMC

• 2 other identifiers: 050001R01MH071205
• Study Type: observational
• Target: 4
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

HIV Infections

Keywords

HIV; AIDS; CNS; brain; affects

Outcome Measures

Primary Outcomes (3)

• 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.

  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.

  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.

  end of study

Study Arms (3)

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 ( cerebrospinal fluid) sampling via intrathecal catheter.

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 Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

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.

You may qualify if:

• (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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Vanderbilt University: lead
• National Institutes of Health (NIH): collaborator

Study Sites (1)

Vanderbilt AIDS Clinical Trials Center

Nashville, Tennessee, 37232-2582, United States

Location

Biospecimen

Retention: SAMPLES WITH DNA

whole blood, plasma, CSF

MeSH Terms

Conditions

HIV Infections; Acquired Immunodeficiency Syndrome

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Slow Virus Diseases

Study Officials

• David W. Haas, MD

  Vanderbilt University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: December 26, 2007
• First Posted: December 31, 2007
• Study Start: March 1, 2006
• Primary Completion: June 1, 2009
• Study Completion: July 1, 2010
• Last Updated: May 28, 2014

Record last verified: 2014-05

Locations

US (1)