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=20) who intend to start ARV
2. ARV-naïve, HIV-positive ≥ 20 year of age without HAD (n=20), who intend to start ARV
3. HIV-negative ≥ 20 year of age (n=20). 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: 20 HAD individuals, 20 CD4-, education-, gender-, and age-matched non-HAD individuals and 20 HIV negativecontrols. 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.

• Thai HAD individuals (n=20 subjects)
• Thai Non-HAD individuals (n = 20 subjects)
• Thai Non-infected individuals (n = 20 subjects)

Inclusion Criteria:

1. 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 assesssment and neuropsychological testing and eligible for inclusion.

2. 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.
3. 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.

Exclution Criteria:

1. Head injury with loss of consciousness greater than 1 hour
2. 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.
3. Inability to provide informed consent or lack of designated surrogate who can provide consent

4. 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
5. 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.
6. Current or recent fevers or meningeal signs suggestive of CNS opportunistic infection.*
7. History of pre-existing neurologic disease to include stroke, multiple sclerosis
8. 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 depresion that is controled and patients with or minor depressive symptoms will be allowed to enroll.
9. Known learning disability including dyslexia.
10. Positive Hepatitis C serology (Hepatitic C Ab)
11. Confusion or other signs and symtoms of metabolic encephalopathy or delirium
12. 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.*
13. Other conditions that could explain neurocognitive decline in the opinion of the investigator such as hypothyroidism, vitamin B12 deficiency or neurosyphilis.
14. Pregnancy.
15. Not willing to take an MRI.