Immunotherapies for HIV Eradication in the CNS Compartment

"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."

"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."

HIV establishes persistent infection in the central nervous system within days of exposure, with virus remaining detectable in cerebrospinal fluid, brain tissue, and CNS-resident immune cells despite decades of antiretroviral therapy. This persistent infection drives chronic neuroimmune dysregulation through microglial activation and astrocyte dysfunction, contributing to depression and neuropsychiatric conditions affecting 30-40% of people with HIV, and HIV-associated neurocognitive disorders in 15-30% of this population. Immunotherapies have proven effective in other CNS conditions, establishing that immune-based strategies can function within the brain. However, broadly neutralizing antibodies administered systemically show limited blood-brain barrier penetration, potentially allowing independent viral evolution in the CNS and creating safety concerns regarding complement-mediated synaptic injury from Fc-effector engagement.

Read at National Institute of Mental Health (NIMH)