Neurodegenerative phagocytes mediate synaptic stripping in Neuro-HIV

SUMMARY

Glial cell activation is a hallmark of several neurodegenerative and neuroinflammatory diseases. During HIV infection, neuroinflammation is associated with cognitive impairment, even during sustained long-term suppressive antiretroviral therapy. However, the cellular subsets contributing to neuronal damage in the CNS during HIV infection remain unclear.

Using post-mortem brain samples from eight HIV patients and eight non-neurological disease controls, the authors of this article, led by GCIR member Professor Doron Merkler, identified a subset of CNS phagocytes highly enriched in LGALS3, CTSB, GPNMB and HLA-DR, a signature identified in the context of ageing and neurodegeneration.

In HIV patients, the presence of this phagocyte phenotype was associated with synaptic stripping, suggesting an involvement in the pathogenesis of HIV-associated neurocognitive disorder.

Taken together, their findings elucidate some of the molecular signatures adopted by CNS phagocytes in HIV-positive patients and contribute to the understanding of how HIV might pave the way to other forms of cognitive decline in ageing HIV patient populations.

Full article: https://doi.org/10.1093/brain/awac102

Why is this article important?

HIV (human immunodeficiency virus) is the virus responsible for AIDS (acquired immunodeficiency syndrome), a condition arising from infection of CD4+ T cells, a crucial arm of the immune system involved in host defenses against infections.

Unfortunately, HIV can gain access to the central nervous system (CNS) very early during primary infection via circulating infected immune cells that can cross the blood-brain barrier. Subsequently, the virus can establish a persistent infection in CNS phagocytes giving rise to a viral reservoir which can be difficult to access for antiretroviral therapy.

Although the incidence of the most severe forms of HIV-associated neurocognitive disorders (HAND) has decreased with the use of highly active antiretroviral therapy, the prevalence of mild to moderate forms of HAND remains high, even in well-treated patients.

The authors of this publication used brain samples from HIV-positive patients to investigate the presence and distribution of neurodegenerative phagocytes and their association with synaptic loss (which correlates with cognitive decline). They observed that neurodegenerative phagocytes can be detected in brain samples from HIV-positive patients and that CNS phagocyte-mediated synaptic loss represents a mechanistic substrate of cognitive impairment in the neuropathology of HIV.

Their results suggest that the neuropathology of HIV and Alzheimer's disease share a similar neurodegenerative signature associated with microglial activation and synaptic loss that could be explored for future therapeutic interventions.

This work is supported by the Swiss National Science Foundation and the European Research Council.

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