Investigating the role of the T cell repertoire in viral neuroinvasion and neuropathology in the face of HIV antiretroviral therapy

About This Grant

Numerous studies have shed light on the capability of T cells in facilitating HIV entry into the central nervous system (CNS) and HIV-associated brain injury (HABI) in the era of combined antiretroviral therapy (cART); yet, one critical question remains - what differentiates and/or predicts T cell behavior in individuals with HABI from those without? Preliminary machine learning has identified unique signatures of viral adaptation in infected peripheral blood T cells from S[imian]IV-infected Rhesus macaques with mild-to-moderate neuroinflammation, begging the question as to whether select viral variants are capable of re-programming T cell migration. On the other hand, T cell migration is dictated by cell differentiation state (e.g., naive vs memory phenotype), and recent evidence indicates this differentiated state can be influenced by T cell receptor (TCR) sequence features. Somatic rearrangement of the genes forming the TCR sequence within an individual results in natural TCR heterogeneity that may not only explain differences in T cell neuroinvasive capabilities across HIV-infected individuals, but may be used to identify individuals who would benefit from therapies used in other T cell-mediated neurological disorders, such as multiple sclerosis. We propose to address the underlying questions of viral and TCR influences on differential T cell migration and neuroinvasion using a multitude of single-cell techniques applied to human tissue and an extensive collection of CNS and peripheral tissues from the macaque model of HIV infection in the presence and absence of T cell trafficking inhibitor - natalizumab. Combining strengths in viral, immunological, and computational research, we propose to tackle these long-standing questions specifically by 1) identifying unique viral and/or T cell properties associated with T cell infiltration in the CNS (Aim 1), 2) characterizing the relationship between viral infection, TCR features, and T cell migration potential (Aim 2), and 3) evaluating the impact of natalizumab on T cell trafficking, viral dynamics, and neuroinflammation (Aim 3). Importantly, recent findings of the role of the complex interplay of viral and T cell genetics in the neurological disorder - multiple sclerosis - point to a phenomenon that may span multiple diseases, indicating the in-depth characterization of this interplay has potentially broader implications than HIV infection.