Functional brain network reorganization in HIV infection

Abstract

Background and Purpose To investigate the reorganization of the central nervous system provided by resting state‐functional MRI (rs‐fMRI), graph‐theoretical analysis, and a newly developed functional brain network disruption index in patients with human immunodeficiency virus (HIV) infection. Methods Forty HIV‐positive patients without neurological impairment and 20 age‐ and sex‐matched healthy controls underwent rs‐fMRI at 3T; blood sampling was obtained the same day to evaluate biochemical variables (absolute, relative, and nadir CD4 T‐lymphocytes value and plasmatic HIV‐RNA). From fMRI data, disruption indices, as well as global and local graph theoretical measures, were estimated and examined for group differences (HIV vs. controls) as well as for associations with biochemical variables (HIV only). Finally, all data (global and local graph‐theoretical measures, disruption indices, and biochemical variables) were tested for putative differences across three patient groups based on the duration of combined antiretroviral therapy (cART). Results Brain function of HIV patients appeared to be deeply reorganized as compared to normal controls. The disruption index showed significant negative association with relative CD4 values, and a positive significant association between plasmatic HIV‐RNA and local graph‐theoretical metrics in the left lingual gyrus and the right lobule IV and V of right cerebellar hemisphere was also observed. Finally, a differential distribution of HIV clinical biomarkers and several brain metrics was observed across cART duration groups. Conclusion Our study demonstrates that rs‐fMRI combined with advanced graph theoretical analysis and disruption indices is able to detect early and subtle functional changes of brain networks in HIV patients.

Gray matter volumes discriminate cognitively impaired and unimpaired people with HIV

“…These markers of AD currently include neurodegenerative metrics obtained from MRI (e.g., less GMV) and PET (e.g., abnormal amyloid and tau depositions; Jack et al, 2018 ). Potential future directions might be to combine the Frascati criteria with emerging neuroimaging markers of HAND, including GMV as demonstrated in the present study, as well as functional MRI ( Ances et al, 2009 , Nguchu et al, 2021 , Plessis et al, 2014 , Hall et al, 2021 , Minosse et al, 2021 ) and magnetoencephalography ( Spooner et al, 2020 , Lew et al, 2018 , Wiesman et al, 2018 , Wilson et al, 2017. , Becker et al, 2012a , Becker et al, 2012b ).…”

Altered large-scale brain network interactions associated with HIV infection and error processing

“…This interpretation is further supported by our observation that HIV-associated RAI reductions were primarily driven by PLWH (vs. HIV− participants) presenting with higher SN-DMN synchrony. Prior work demonstrating altered network organization among PLWH ( Abidin et al, 2018 ; Hall et al, 2021 ; Minosse et al, 2021 ) has also often highlighted alterations involving the DMN ( Thomas et al, 2015 ; Zhuang et al, 2017 ). For example, one study found that treatment naïve PLWH displayed significantly reduced rsFC within the DMN when compared with controls ( Zhuang et al, 2017 ), while another study utilizing graph theoretic metrics found alterations in closeness centrality (a metric indicating connectiveness with the rest of the brain) within the DMN and frontoparietal network among PLWH ( Thomas et al, 2015 ).…”

The role of IFN-γ production during retroviral infections: an important cytokine involved in chronic inflammation and pathogenesis

“…People living with HIV (PLWH) can also have neurological symptoms. The virus can cross the blood-brain barrier during the acute phase, with the migration of infected monocytes from the bloodstream into the CNS and infect neighbouring cells, such as microglia and astrocytes 34 . The antiviral cytokines present in the brain during infection control the viral replication in the CNS 35 .…”

“…Neurons are not killed directly by a viral infection, but viral proteins induce the production of cytokines such as IFN-γ, TNF-α, and IL-1β which are neurotoxic. A study found that the JAK/STAT pathway, a key regulator of inflammatory and apoptotic signalling, is elevated in HIV-1-infected brains progressing to HAND 34 . This pathway can be inhibited by the epigallocatechin-3-gallate (EGCG) present in green tea, resulting in a decrease of inflammatory cytokines and the consequent mitigation of neuronal damage in the cortical regions of mouse brains, as compared to controls 45 .…”

“…These observations suggest the use of IFN-γ for monitoring patients that tend to progress to HAND and it can be an important therapeutic target, as an adjunct to ART, to prevent it. Immunological pathways that activate the production of pro-inflammatory cytokines and chemokines should be investigated in order to help in the development of a treatment strategy to prevent patients from becoming dependent 34,46 . Some people remain negative for HIV infection despite having unprotected sex with viremic HIV-positive patients.…”