Immunotherapies for HIV Eradication in the CNS Compartment

Presenter

Vasudev Rao, MBBS, M.S.
Division of AIDS Research, NIMH

Goal

The goal of this concept is to generate comprehensive evidence to determine whether immunotherapeutic strategies, including broadly neutralizing antibodies (bNAbs) and antibody-derived constructs, can safely and effectively target HIV persistence within the central nervous system (CNS) compartment while mitigating neuroimmune dysfunction and improving mental health outcomes.

Rationale

HIV establishes persistent CNS infection within days of initial exposure, with virus detected in cerebrospinal fluid (CSF), brain parenchyma, and CNS-resident immune cells. Even with decades of suppressive antiretroviral therapy, HIV DNA and RNA persist in the CNS, driving chronic neuroimmune dysregulation through microglial activation, astrocyte dysfunction, and elevated inflammatory mediators. Depression and other neuropsychiatric conditions affect 30–40% of people with HIV, and HIV-associated neurocognitive disorders (HAND) are prevalent 15–30% of this population; both driven in part by persistent neuroimmune dysregulation.

Immunotherapies have demonstrated clinical efficacy in multiple central nervous system conditions, including neuroinflammatory and oncologic disorders, establishing proof of principle that immune-based strategies can be engineered to function within the CNS. Achieving an HIV cure similarly requires elimination of viral persistence across all anatomic compartments, yet the CNS remains comparatively understudied in remission-directed research. bNAb-based immunotherapies show that sustained ART-free viral suppression is biologically achievable, but key CNS barriers remain. Systemically administered bNAbs exhibits limited blood–brain barrier (BBB) penetration, could enable CNS viral populations evolve independently (compartmentalization), and Fc-effector engagement in CNS myeloid cells introduces a safety-efficacy tradeoff between infected-cell clearance and complement-mediated synaptic injury. Without well understood CNS-targeted approaches, systemic interventions risk leaving residual anatomic reservoirs and ongoing neuroimmune dysfunction that perpetuate both viral persistence and mental health burden.

Through a biphasic, milestone-driven program, the proposed concept would support research that (1) evaluates immunotherapy penetration across the BBB and distribution within CNS tissues; (2) assesses impact on CNS viral reservoirs, including infected microglia and perivascular macrophages; (3) characterizes effects on neuroimmune biomarkers and microglial activation; (4) assesses the impact on depression, anxiety, and neuropsychiatric outcomes; (5) identifies mechanisms through which immunotherapies modulate both viral persistence and immune-mediated neuropsychiatric symptoms; (6)Supports development of novel immunotherapies with demonstrable CNS target engagement in vivoand (7) establishes CNS-specific safety profiles including Fc-effector and complement-mediatedneurotoxicity risk. By addressing these above objectives, this concept would inform the development ofcure strategies that achieve sustained HIV remission while simultaneously improving neurologic,cognitive, and mental health in people living with HIV.