Important role of microglia in HIV-1 associated neurocognitive disorders and the molecular pathways implicated in its pathogenesis

Abstract

The development of effective combined anti-retroviral therapy (cART) led to a significant reduction in the death rate associated with human immunodeficiency virus type 1 (HIV-1) infection. However, recent studies indicate that considerably more than 50% of all HIV-1 infected patients develop HIV-1-associated neurocognitive disorder (HAND). Microglia are the foremost cells infected by HIV-1 in the central nervous system (CNS), and so, are also likely to contribute to the neurotoxicity observed in HAND. The activation of microglia induces the release of pro-inflammatory markers and altered secretion of cytokines, chemokines, secondary messengers, and reactive oxygen species (ROS) which activate signalling pathways that initiate neuroinflammation. In turn, ROS and inflammation also play critical roles in HAND. However, more efforts are required to understand the physiology of microglia and the processes involved in their activation in order to better understand the how HIV-1-infected microglia are involved in the development of HAND. In this review, we summarize the current state of knowledge about the involvement of oxidative stress mechanisms and role of HIV-induced ROS in the development of HAND. We also examine the academic literature regarding crucial HIV-1 pathogenicity factors implicated in neurotoxicity and inflammation in order to identify molecular pathways that could serve as potential therapeutic targets for treatment of this disease. KEY MESSAGES Neuroinflammation and excitotoxicity mechanisms are crucial in the pathogenesis of HAND. CNS infiltration by HIV-1 and immune cells through the blood brain barrier is a key process involved in the pathogenicity of HAND. Factors including calcium dysregulation and autophagy are the main challenges involved in HAND.

Significant higher‐level C‐C motif chemokine ligand 2/3 and chemotactic power in cerebral white matter than grey matter in rat and human

“…Apart from higher number of PC in the WM, we also observed nodular lesions formed by microglia nodules (MN) that were more prevalent in the WM than in the GM of the SIV-infected brain (Zhang et al, 2019), suggesting involvement of microglia in virus-induced WM injury as reported by many other studies (Borrajo et al, 2021;Wallet et al, 2019). The formation of MN in normal appearing WM was also observed in early stage of MS, which occurred before T-cell infiltration (Singh et al, 2013).…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…The increased and chronic inflammatory status in the brain may contribute to neurodegeneration due to increased neuronal cell death and reduced neurogenesis, reduced remodeling and irreparable damage to the neuronal network, resulting in an enhanced or accelerated brain aging process. In the context of microglia and viral infection, most research has been done in HIV, where the association has been shown for neurocognitive decline [ 127 , 128 , 228 , 246 ]. However, there is little information available about the cellular and molecular mechanisms that contribute to or influence the chronic HIV infection and corresponding involvement of microglia, which requires more future research.…”

“…The detailed cellular and molecular mechanisms responsible for HAND have still to be elucidated [ 124 , 125 ]. However, chronic HIV infection results in corresponding neuroinflammation with activation of microglia and astrocytes [ 126 , 127 , 128 ]. There is also increasing evidence that there is production and deposition of beta-amyloid peptide, similar to Alzheimer’s disease [ 129 , 130 ].…”

“…Secondly, microglia may respond with excessive production of neurotoxic factors including oxygen radicals (ROS) [ 231 ]. ROS production by microglia has been reported in the context of brain infection with various viruses [ 127 , 232 , 233 , 234 , 235 ]. ROS has been shown to contribute to neuroinflammation, neuronal cell death and corresponding neurodegeneration, thus enhancing brain aging [ 236 , 237 , 238 ].…”

Neurological complications during HIV infection

“…memory and executive functions [8]. Because HIV replication in the CNS occurs principally in microglia (the resident macrophage-type cells), is thought that both, direct effects of viral proteins, and indirect effects mediated by microglia activation and secretion of neurotoxic products can contribute to neuronal damage [9,10]. However, the causes for such neurological dysfunctions are diverse and will be discussed in this review.…”