HIV-1 Specific Immune Responses in Thai Individuals With HIV Dementia

A total of 60 participants will be enrolled. They will be in 3 groups

1. ARV-naïve, HIV-positive ≥ 20 year of age with HAD (n=25) who intend to start ARV
2. ARV-naïve, HIV-positive ≥ 20 year of age without HAD (n=25), who intend to start ARV
3. HIV-negative ≥ 20 year of age (n=10). The protocol team will work with the primary care physician to ensure that the subjects receive standard HIV and ARV care; however, initiation of ARV is not a requirement of the study and ARV will not be provided by the study.

Participant accrual will include 10-15 participants per year. HIV-positive subjects will be tentatively enrolled in HAD vs. non-HAD groups by the enrolling neurologist and subsequently confirmed to that group by a consensus conference held every 6 months by the study neurologists. In cases of disagreement, cases will be re-assigned to the consensus conference determination and recruitment will continue. An external validation consensus conference will be conducted as well every 6-12 months to monitor correct assignment of the level of impairment.

This application focuses on the role of cellular immune responses in HIV dementia (HAD) versus non-HAD individuals in a cognitively characterized cohort followed for one year.

Increasing evidence links strong CD4+ T helper function to robust CD8+ CTL responses. HIV-1-infected individuals who are able to maintain strong HIV-1 specific T cell responses have better clinical outcomes and rarely develop neurological signs or symptoms. Monocyte/macrophage (M/M) infiltration into the white matter of the brain is a hallmark of HAD; however, the mechanisms by which M/M are recruited to the brain are not clearly understood. We hypothesize that the loss of specific HIV-1 T cell response results in activation/dysregulation of M/M leading to their accumulation in the brain.

To test this hypothesis will characterize Thai HIV-1-infected individuals as follows: 25 HAD individuals, 25 CD4-, education-, gender-, and age-matched non-HAD individuals and 10 HIV negative controls. We will then: 1) define CD4+ and CD8+ T cell function by evaluating HIV-1 specific responses in HAD vs. non-HAD groups; 2) simultaneously correlate these responses to M/M subpopulation cell number, percentage, and immune function; 3) correlate these responses to HIV-1 proviral load and autologous viral sequences (viral escape sequences and HIV quasispecies); and 4) evaluate the impact of ARV on dementia related to changes in immunological responses. Since little is known of the interaction between CD4+ T helper responses, CTL function, and the level of M/M subpopulation activation in the neuropathogenesis of HAD, this innovative study will elucidate the role of HIV-1 specific immune responses in HAD and provide new insights into HIV-1 neuropathogenesis and its relationship to peripheral immune responses, potentially opening exciting new areas for further investigation.

Inclusion Criteria:

Group Thai HAD individuals

• 20 years of age

  • not currently receiving nor have ever received antiretroviral medications
  • not explained by opportunistic infections or causes other than HIV on the basis of clinical assessment and neuropsychological testing and eligible for inclusion.

Group Thai Non-HAD individuals

• will be matched with a seropositive Thai patient with similar age (same decade), education (less than high school degree, high school degree +/- some college, college degree +), gender, and CD4 group
• HIV positive
• not currently receiving nor have ever received antiretroviral medications.

Group Thai Non-HAD individuals will be matched with a Thai seronegative patient by age (same decade), and education (less than high school degree, high school degree +/- some college, college degree+), and gender.

Exclusion Criteria:

• Head injury with loss of consciousness greater than 1 hour
• Current or past illicit drug use (less then 5 years) or positive drug screen for amphetamine, methamphetamines, cocaine, marijuana, or narcotics at either screening or entry.
• Inability to provide informed consent or lack of designated surrogate who can provide consent
• The following laboratory values:
• PT/PTT > the upper limit of normal (ULN) or INR > 1.1
• Hemoglobin < 9.0 mg/dL
• ALT > 5x ULN
• serum creatinine > 2x ULN or creatinine clearance < 30 cc per min by Cockroft-Gault formula
• Acute illness within 30 days prior to entry, persistent and active AIDS- defining opportunistic infection or autoimmune disease. Stable treated opportunistic infections on maintenance therapy, minor infections such as oral thrush and Kaposi's Sarcoma limited to the skin will be allowed.
• Current or recent fevers or meningeal signs suggestive of CNS opportunistic infection.*
• History of pre-existing neurologic disease to include stroke, multiple sclerosis
• History of psychiatric illness including schizophrenia, bipolar disorder, anxiety disorder, panic attacks, or post traumatic stress disorder. Patients with active major depression will be excluded as well - patients with past depression that is controlled and patients with or minor depressive symptoms will be allowed to enroll.
• Known learning disability including dyslexia.
• Positive Hepatitis C serology (Hepatitic C Ab)
• Confusion or other signs and symptoms of metabolic encephalopathy or delirium
• Mass consistent with opportunistic infection or tumor on CT or MRI of the head, or focal neurological deficit on examination consistent with possible brain lesion.*
• Other conditions that could explain neurocognitive decline in the opinion of the investigator such as hypothyroidism, vitamin B12 deficiency or neurosyphilis.
• Pregnancy.
• Not willing to take an MRI.