Discovering novel therapeutic options for HIV-Associated Neurocognitive Disorders (HAND) by exploiting the role of the alpha4 beta1 integrin (VLA-4)
Purpose
HIV-Associated Neurocognitive Disorders (HAND) are an important clinical complication of HIV infection and can result in an array of cognitive behavioral and motor deficits. With an estimated prevalence of 30-45 0n the combination antiretroviral therapy (cART) era HANDs are pervasive with significant potential to adversely affect quality of life morbidity and mortality. At present no adjunctive therapies for HAND exist making the need for their development of paramount clinical importance. HIV is postulated to cross the blood-brain barrier (BBB) via the infiltration of infected monocytes CD4+ T lymphocytes or as cell-free virus. The integrin α4β1 (VLA-4) is an integrin dimer often referred to as a marker of CNS homing. VLA-4 is widely expressed on leukocyte plasma membranes and binds the integrin receptor vascular cell adhesion molecule-1 (VCAM-1) on endothelial cells. Antibodies against the α4 subunit of VLA-4 have been shown to block monocyte/macrophage and SIV virus traffic to the brain and stabilize CNS injury in a rhesus macaque model of HIV infection. We hypothesize that VLA-4 expressing leukocytes are enriched for cells trafficking to the CNS and the transcriptional profiling of these cells in the periphery of HAND patients can identify genes signaling pathways and ultimately small molecule candidates for therapeutic development in HAND. To explore this hypothesis we performed preliminary experiments employing transcriptome sequencing (RNA-seq) of purified VLA-4 expressing CD14+ monocytes and CD4+ T cells from the PBMC of chronically infected HIV positive subjects on suppressive cART. We identified a number of highly differentially expressed genes between individuals with HAND (n=6) and those with normal neurocognitive function (NCN) (n=6) including some (e.g. CCL2) also referred to as monocyte chemoattractant protein 1 (MCP-1) that have been long implicated in HAND pathogenesis. This led to a preliminary "HAND gene-expression signature". These exciting results will be expanded upon in this 3-year proposal. Here we will seek to: AIM 1) Enroll and immunologically phenotype a larger cohort of HIV-positive individuals. We will perform neuropsychological testing (NPT) to identify 15 individuals with HAND and 15 individuals with NCN. Novel flow cytometry experiments will determine the distribution of VLA-4 expression on leukocytes from paired cerebrospinal fluid (CSF) and blood in treated suppressed HIV. A third control group of 15 HIV-negative individuals will be similarly characterized. Potential relationships between levels of VLA-4 expression and NPT performance will be examined through multivariate modeling; and AIM 2) Validate our preliminary HAND gene-expression signature. We will perform RNA-seq analysis on RNA from VLA-4 expressing CD14+ monocytes and CD4+ T cells from peripheral blood obtained from all participants enrolled in AIM 1 apply GSEA pathway analysis and confirm candidate genes using q-PCR. In this way we expect to identify robust candidate disease biomarkers and exploitable molecular targets for therapy. Additionally using the Broad Institute Connectivity map we will identify therapeutic candidate molecules for reversal of the HAND signature in future studies. In summary we propose a rational integrated clinical systems biology molecular approach that has the potential to transform the treatment landscape for an important HIV co-morbidity.
Condition
- Human Immunodeficiency Virus
Eligibility
- Eligible Ages
- Between 18 and 74
- Eligible Genders
- All
- Accepts Healthy Volunteers
- Yes
Inclusion Criteria
- HIV positive individuals 18 - 74 years of age male or female OR HIV negative individuals 18-74 years of age male or female
- For both HIV negative and HIV positive participants: English language fluency
- For HIV negative and HIV positive participants: Ability and willingness of participant to give written informed consent
- For both HIV negative and HIV positive participants: If female negative Beta-HCG (human chorionic gonadotropin) pregnancy test
- For both HIV negative and HIV positive participants: Agrees to the undergo a spinal tap and have blood samples collected for research purposes
- For HIV negative participants: Non-reactive HIV test at screening/enrollment
- For HIV positive participants: Positive HIV-1 serology treatment for at least one year with combination antiretroviral therapy plasma HIV-1 RNA levels below 50 copies/ml for at least 6 months prior to screen visit as evidenced by lab results from their primary care provider
Exclusion Criteria
- For all participants: Bleeding diathesis or current use of anticoagulants
- For all participants: History of head injury with loss of consciousness greater than thirty minutes
- For all participants: History of severe neurological (e.g. multiple sclerosis seizure disorder) or Diagnostic and Statistical Manual Five Edition (DSM-V) pschyiatric illness that affects cognitive functioning (e.g. schizophrenia biopolar affective disorder)
- For all participants: Current diagnosis of major depression disorder as assessed by the patient health questionnaire nine item depression scale (PHQ-9) and not on stable antidepressant medication > 30 days
- For all participants: DSM-V criteria for severe alcohol/substance use disorder within 1 year prior to screen (excluding marijuana)
- For all participants: History of clinically significant cardiac disease such as myocardial infarction congestive heart failure or cardiac arrhythmia requiring treatment atherosclerosis
- For all participants: Significant renal disease poorly controlled diabetes autoimmune disorders chronic inflammatory disease
- For all participants: Any other clinical conditions or prior to enrollment treatment in the opinion of the investigator would make the subject unsuitable for the study or unable to comply with the requirements of the protocol
- For all participants: Allergy to lidocaine
- For all participants: Laboratory values obtained within 45 days prior to study entry: PT/PTT > 1.5 x control Positive Hepatitis C antibody (HepC Ab+) Positive Hepatitis B surface antigen (Hbs Ag+) Absolute neutrophill count (ANC) < 500 cells/mm3 Platelet count < 80000/mm3 Hemoglobin < 9.0 g/dl Calculated creatinine clearance < 60 mL/minute AST (SGOT) ALT (SGPT) or alkaline phosphatase > 5.0 times the upper limit of normal (ULN) Total bilirubin > 2.5 x ULN (isolated Bilirubin > 2 x ULN is acceptable if direct Bilirubin is < 35%
- Serologic evidence of untreated syphilis
- Body mass index (BMI) > 40 kg/m2
- Individuals who are unable to safely tolerate a lumbar puncture due to physical limitation or condition (e.g. severe scoliosis spinal abscess)
- Prolonged steriod/hormonal replacement therapy
Study Design
- Phase
- Study Type
- Observational
More Details
- Status
- Recruiting
- Sponsor
- Rockefeller University