Neuroinflammation Associated with Proviral DNA Persists in the Brain of Virally Suppressed People with HIV

Sarah J Byrnes¹Janna Jamal Eddine¹Jingling Zhou¹Emily Chalmers¹Emma Wanicek²Narin Osman¹Trisha Anne Jenkins¹Michael Roche^1,3Bruce James Brew^4,5Jacob D Estes^1,6Thomas A Angelovich^1,3,7Melissa Jayne Churchill^1,7*

• ¹ATRACT Centre, School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia
• ²School of Science, RMIT University, Melbourne, Victoria, Australia
• ³Department of Infectious Diseases, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
• ⁴St Vincent’s Hospital Sydney, Darlinghurst, New South Wales, Australia
• ⁵University of New South Wales, Kensington, New South Wales, Australia
• ⁶Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, Oregon, United States
• ⁷Life Sciences Discipline, Burnet Institute, Melbourne, Victoria, Australia

Despite viral suppression with antiretroviral therapy (ART), people with HIV (PWH) continue to exhibit brain pathology and ~20% of individuals develop HIV-associated neurocognitive disorders. However, the state of cellular activation in the brain of virally suppressed (VS) PWH, and the impact of local viral reservoirs on cellular activation are unclear. Using multiplex immunofluorescence imaging here we demonstrate that frontal cortex brain tissue from both non-virally suppressed (nVS; n=17) and VS PWH (n=18) have higher frequencies of astrocytes and myeloid cells expressing interferon-inducible Mx-1 and proinflammatory TNFα relative to HIV-seronegative individuals (P<0.05 for all). The frequency of TGF-β1+ cells were also elevated in brain tissue from both nVS and VS PWH, which may support active immunoregulatory responses despite ART. Importantly, the frequency of Mx1+ myeloid cells correlated with levels of total HIV DNA, intact and 5' defective HIV proviral DNA (P<0.05 for all) in the brain of VS PWH. These findings demonstrate that cell activation persists in the brain of VS PWH and is associated with HIV DNA in the brain which may contribute to neuropathology.