The brain and HIV-1 infection : inflammation processes in humanized BLT mice and neurological changes

Advances in anti-retroviral therapy (ART), policies, prevention programs and care distribution have led to considerable decreases in the number of AIDS-defining illnesses and related deaths, with accompanying increases in life expectancy. Concurrently, people living with HIV (PLWH) face novel challenges. For example, age- and HIV-related inflammation contribute to an increased risk of neurocognitive impairment. In fact, approximately 50% of ART-treated individuals experience HIV-associated neurocognitive disorders (HAND), and the prevalence of HAND is increasing. This suggests the need for continued improvement in research models to better understand HAND pathogenesis and pathophysiology. Our research aimed to investigate the subclinical and clinical features of HAND using the humanized bone marrow liver thymus (huBLT) mouse model of HIV-1 infection. Here, we report the infiltration of human immune cells and virus in the brains of huBLT mice, with monocyte-macrophages colocalizing with HIV-1 p24 protein. Brain infection associated with distinct profiles of interferon-responsive genes and decreased expression of mouse tight junction genes, occludin and claudin-5, markers of blood-brain barrier permeability. Similarly, infected huBLT mice had significantly poorer performance in the accelerating rotarod test, indicating impaired balance and motor coordination which are characteristic symptoms of HAND, while procedural learning remained unaffected. Infected mice also displayed hyperactive behaviors in the open field test, reminiscent of mania-like behaviors observed in HIV-1-infected individuals. Finally, preliminary results showed evidence for pathologic features of RNA metabolism and reduced neuronal cell health. While mouse models have previously been used to evaluate HAND, none have characterized the clinical manifestations in huBLT mice, which have mucosal reconstitution and therefore display biologically relevant compartments for the study of HIV-1 pathogenesis. Our results thus far underscore the huBLT mouse model of infection as a suitable tool for the characterization of HIV-1-related motor and mood manifestations in the context of neuroinflammation and neuronal injury, and the exploration of HAND targets. Ultimately, the elucidation of key players underlining subclinical and clinical complications of neuroinflammation during HIV-1 infection will inform the development of novel research approaches to bridge the gap between current preventative and diagnostic tools, the poor brain penetrance of many current ART and the increasing prevalence of HAND.