Assessment of the HIV CNS Reservoir, Neurological and Neuro-cognitive Effects, and Source of Rebound HIV in CNS
Condition: Acute HIV Infection; HIV CNS Involvement
MeSH terms: HIV Infections
Study type: Observational

Summary: 
      This study aims to describe in depth the CNS, CNS HIV reservoir and CNS viral rebound in
      consenting SEARCH 019 subjects prior to, during and after the SEARCH 019 study intervention
      (VHM + ART or ART only), at 1) baseline, 2) end of study intervention and start of ART
      interruption, 3) viral rebound (if occurring) or mid-way during observed ART interruption,
      and 4) at the end of ART interruption. Study SEARCH 026 itself does not employ any
      therapeutic interventions. However, consenting subjects will participate in lumbar puncture,
      non-contrast MRI + MRS, and neuropsychological testing at at least three and at most four
      time points. Any of the 15 subjects to be enrolled in SEARCH 019 may consent to study SEARCH
      026 participation and hence a maximum of 15 subjects may enroll. As this is a sub-study, data
      will be shared from study SEARCH 019 and no interventions (venipunctures) will be repeated
      unnecessarily.
    

Detailed description: 
      1. Clinical 1.1 Neurological exam: SEARCH employs the AIDS Clinical Trials Group
           (ACTG)-derived HIV macroneurological examination, a physician rated symptoms assessment
           of cognitive features typical of HIV-associated neurocognitive disorder (HAND) and
           peripheral neuropathy.

           1.2 Neuropsychological assessments: SEARCH employs the HIV neurocognitive battery
           originally developed by Maj et al. designed to minimize cultural bias and tested in
           Bangkok. All subjects will have the full SEARCH battery as previously published,
           avoiding evaluations following invasive procedures. All testing is completed by
           certified nurse-psychometrists. Data are compared to a normative set of 500
           HIV-negative, healthy, community dwelling Thais and stratified by age and educational
           attainment to define standardized z-scores. A psychiatric inventory mirrors that used
           for RV254 and has broad Thai validity data, and research nurses perform a functional
           assessment based on the Clinical Dementia Scale.

           1.3 Lumbar puncture: Lumbar punctures are completed per standard clinical procedures
           using a Sprotte® (pencil-point) needle to minimize complications. Standard assessments
           of CSF and serum, protein and cell count are completed and approximately 20cc are
           collected and ultra-centrifuged. Cell pellets of CSF will be cryopreserved for future
           potential studies, with subject consent. Supernatants are divided into 0.5cc aliquots,
           and frozen to -80oC on the same day. CSF VDRL/RPR will be assessed at baseline for those
           with positive serology in SEARCH 019 and in follow-up if a new positive serology is
           reported in SEARCH 019 or if subject was CSF positive at baseline. Participant
           hospitalization for any research-related adverse events requiring admission will be
           arranged, if needed.

           1.4 Neuro-imaging: Imaging studies will be performed at the Chulalongkorn University
           Hospital which is 100 meters from the TRCARC in Bangkok. These studies will take up to
           one hour maximum MRI scanner time for each subject and may include brain MRI, MRS, DTI
           and resting state functional MRI (fMRI). MRI and MRS are non-invasive methods to detect
           brain pathology (MRI) and to determine the in-vivo concentration of brain metabolites
           (MRS). DTI is a sensitive non-invasive magnetic resonance technique to analyze the
           three-dimensional diffusion of water within brain tissue. The diffusion of water within
           the brain is highly dependent on the underlying micro-architecture of the surrounding
           tissue, which is affected by both normal physiological processes (such as aging) as well
           as local neuropathological disease processes, such as those seen with HIV infection.
           Resting state functional MRI (fMRI) reveals patterns of activation of brain networks and
           is a sensitive measure of brain function prior to structural and anatomical changes
           detected by other methods. Gadolinium will not be used for research purposes.

        2. Laboratory (all pertaining to CSF)

      2.1 Measurement of soluble markers: Commercial ELISA kits (Human Quantikine ELISA kits; R&D
      Systems, Inc.) and Millipore Luminex assays will be used following manufacturer's
      instructions at the Yale Immune Monitoring Core Laboratory. Soluble biomarkers associated
      with immune activation and neurocognitive impairment will be measured, including CSF
      neopterin, MCP-1, sCD14, IL-6, sCD163, and IP-10.

      2.2 CSF virology Assays: HIV RNA standard quantitation will be completed using the Roche
      COBAS/Amplicor HIV-1 Viral Load v2.0 assay, with a lower limit of quantitation of 20cps/mL.
      Single Copy Assay (SCA) HIV RNA quantitation in the setting of ART will be performed using
      5-10 ml of CSF. In addition, cell associated HIV-DNA (total, integrated and 2LTR circles in
      total CD4+ T cells will be assessed at CRC-CHUM.

      2.3 TCR repertoire and avidity of HIV-specific CD8+ T cells in CSF: These may be measured in
      a subset of samples at VGTI Florida. For the repertoire assay, CSF cell pellets will be
      polyclonally expanded, and the TCR repertoire will be determined followed by TCR sequencing
      as previously described. For TCR avidity, T cell clones corresponding to the dominant
      clonotypes will be generated in vitro to measure their functional sensitivity. The
      HIV-specific CD8+ T cells clones generated by expansion in the presence of PHA, IL-2 and
      irradiated feeders will be sequenced for their TCR and will be tested for their TCR
      functional sensitivity.

      2.4 Management of Subjects Resuming ART: If the decision is made to reinitiate ART as per
      SEARCH 019 ART resumption criteria, then the study visit before ART resumption will be
      considered this study's final visit and all procedures scheduled for end of study will be
      conducted at that visit.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Any of the 15 subjects to be enrolled in SEARCH 019 may consent to study SEARCH 026
        participation and hence a maximum of 15 subjects may enroll.
      
Biospecimen description: 
      HIV RNA standard quantitation will be completed using the Roche COBAS/Amplicor HIV-1 Viral
      Load v2.0 assay, with a lower limit of quantitation of 20cps/mL. Single Copy Assay (SCA) HIV
      RNA quantitation in the setting of ART will be performed using 5-10 ml of CSF. In addition,
      cell associated HIV-DNA (total, integrated and 2LTR circles in total CD4+ T cells will be
      assessed at CRC-CHUM.