The Role of Monocyte/Macrophages in Central Nervous System Infection with SIV-induced Neuropathogenesis

Abstract

Neuropathogenesis of HIV-associated neurocognitive disorders (HAND) is likely instigated by chronic immune activation in response to residual infection in the central nervous system (CNS), where combined antiretroviral therapy (cART) has limited access. Monocyte/macrophages (Mo/Mϕ) constitute the predominant population of infected cells in the CNS and play a major role in HIV-induced neuropathogenesis. Emergence of compartmentalized HIV subpopulations in the brain corresponds with accumulation of HIV-infected Mo/Mϕ and is consistent with acquired immune deficiency syndrome (AIDS)-related neuropathology. We used a rhesus macaque model of neuroAIDS to elucidate the role of Mo/Mϕ in establishing CNS infection and the emergence of compartmentalized virus in the brain. To do this, we: 1) performed phylogenetic analysis of viral sequences from peripheral and CNS compartments and determined the incidence of Mo/Mϕ infection in CNS tissues to identify sources of CNS viral subpopulations that emerge with AIDS-related neuropathology; 2) optimized a method for obtaining single genome viral sequences from Mo/Mϕ populations extracted from tissues and 3) performed phylogenetic analysis of viral sequences from bone marrow (BM) and CNS Mo/Mϕ and determined the incidence of Mo/Mϕ infection in the BM to assess whether BM Mo/Mϕ are sources of infected Mo/Mϕ that accumulate in the CNS with AIDS-related neuropathology. We found that animals with AIDS-related neuropathology had a higher incidence of Mo/Mϕ infection and compartmentalized SIV subpopulations in CNS tissues compared to animals without neuropathology. Additionally, CSF virus, which is used to assess the presence of CNS virus compartmentalization in living patients, was not compartmentalized even with significant compartmentalization in the brain and severe AIDS-related neuropathology (Chapter 2). Relative to animals without CNS pathology, animals with AIDS-related neuropathology had a higher incidence of Mo/Mϕ infection in the BM and viral sequences from BM and CNS perivascular Mo/Mϕ clustered with sequences from trafficking monocytes and CNS tissues (Chapter 4). The results suggest that infected Mo/MΦ in CNS tissues are sources of compartmentalized virus and that infected Mo/Mϕ in the BM are sources of infected Mo/Mϕ that accumulate in the CNS with AIDS-related neuropathology. In summary, the data in this dissertation suggest that targeting Mo/Mϕ may prevent CNS infection and inflammation associated with HIV-induced neuropathogenesis.