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

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.

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.