Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management

Abstract

People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.

Fig. 1 |. Overview of factors contributing to neurocognitive impairment in people living with HIV with viral suppression.

HIV proteins, such as Tat, which continue to be produced even when HIV replication is suppressed by antiretroviral therapy, are toxic to neurons and glial cells. In addition, HIV interacts with the host to produce deleterious immune responses. Particularly important here is the innate immune response, mediated in large part by interferon signalling and myeloid cell activation, which results in the production of neurotoxic inflammatory mediators, mitochondrial dysfunction and oxidative stress, impaired autophagy and ultimately neurodegeneration, leading to neurocognitive impairment. Additional contributing factors are comorbidities, such as insulin resistance, and visceral adiposity as well as toxicities of antiretroviral medications. Addressing these alterations might influence the long-term course of brain disease associated with HIV. LTR, long terminal repeat; NfL, neurofilament light; MAP2, microtubule associated protein 2; SYN, synaptophysin; TNF, tumour necrosis factor.

Fig. 2 |. Hypothetical model of HIV-mediated myeloid cell and neuronal dysfunction in HIV-associated NCI.

HIV-infected monocytes transmigrate from the peripheral blood to the brain. HIV-infected perivascular macrophages and microglia respond by releasing cytokines that further activate microglia and astrocytes. This eventually leads to neuronal dysfunction, as evidenced by impairment of synaptic transmission, disturbed mitochondrial bioenergetics and, eventually, neurocognitive impairment (NCI). BBB, blood–brain barrier.