The Rockefeller University

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% in 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 a4ß1 (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 a4 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