Brain alterations within the first 100 days of <scp>HIV</scp> infection

Ragin, Ann B.; Wu, Ying; Gao, Yi; Keating, Sheila M.; Du, Hongwu; Sammet, Christina L.; Kettering, C; Epstein, Leon G.

doi:10.1002/acn3.136

Cited by 90 publications

(102 citation statements)

References 45 publications

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“…42 Often decreases in FA have been seen in HIV+ individuals compared to HIV- controls. 15,18,33,43-46 While we observed a decrease in FA for HIV+ individuals using DTI, DBSI revealed that observed changes in DTI may in fact reflect the continued presence of inflammation. Inflammation can appear as axonal loss from reduced diffusion along the primary direction yielding a concurrent reduction in FA.…”

Section: Discussionmentioning

confidence: 54%

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Strain

Burdo

Song

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Inflammation occurs after HIV infection and persists despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI), measures HIV associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis Spectrum imaging (DBSI) derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI and DBSI derived fractional anisotropy (FA) maps were processed with tract based spatial statistics for comparison between both groups. Cellularity was assessed with regards to age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared to clinical (HAART duration) and laboratory measures of disease (e.g. CD4 cell current and nadir). NP was similar for both groups. DTI derived FA was lower in HIV+ compared to HIV- individuals. In contrast, DBSI derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.

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Section: Discussionmentioning

confidence: 54%

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Strain

Burdo

Song

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…PC5 is rich in the cerebral cortex and dentate gyrus, while PACE4 is particularly abundant in the cerebellum. Notably, the frontal cortex and the hippocampus are major sites of motor and/or cognitive functions, which are selectively damaged in HAND (11). Although indicative of coexpression, this does not prove that the PAR1 and PC proteins are colocalized intracellularly.…”

Section: Figmentioning

confidence: 99%

“…HIV infects the central nervous system soon after primary infection (11) and establishes a tissue reservoir by productively infecting brain myeloid cells, which eventually leads to neurocognitive impairment in a subset of patients (reviewed in reference 12). HIV-associated neurocognitive disorder (HAND) represents a daunting and ongoing challenge in the diagnosis and care of people with HIV/AIDS.…”

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confidence: 99%

Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

Kim

Zekas

Lodge

et al. 2015

Molecular and Cellular Biology

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eThe proprotein convertases (PCs) furin, PC5, PACE4, and PC7 cleave secretory proteins after basic residues, including the HIV envelope glycoprotein (gp160) and Vpr. We evaluated the abundance of PC mRNAs in postmortem brains of individuals exhibiting HIV-associated neurocognitive disorder (HAND), likely driven by neuroinflammation and neurotoxic HIV proteins (e.g., envelope and Vpr). Concomitant with increased inflammation-related gene expression (interleukin-1␤ [IL-1␤]), the mRNA levels of the above PCs are significantly increased, together with those of the proteinase-activated receptor 1 (PAR1), an inflammation-associated receptor that is cleaved by thrombin at ProArg 41 2 (where the down arrow indicates the cleavage location), and potentially by PCs at Arg 41 XXXXArg 46 2. The latter motif in PAR1, but not its R46A mutant, drives its interactions with PCs. Indeed, PAR1 upregulation leads to the inhibition of membrane-bound furin, PC5B, and PC7 and inhibits gp160 processing and HIV infectivity. Additionally, a proximity ligation assay revealed that furin and PC7 interact with PAR1. Reciprocally, increased furin expression reduces the plasma membrane abundance of PAR1 by trapping it in the trans-Golgi network. Furthermore, soluble PC5A/PACE4 can target/disarm cell surface PAR1 through cleavage at Arg 46 2. PACE4/PC5A decreased calcium mobilization induced by thrombin stimulation. Our data reveal a new PC-PAR1-interaction pathway, which offsets the effects of HIVinduced neuroinflammation, viral infection, and potentially the development of HAND.

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“…One prior study revealed reduced total cortical volume and enlarged third ventricle in PHI, though the study included HIV+ individuals receiving cART [6, 7]. Thus, the natural course of untreated HIV-dependent volume changes is not established, as early initiation of cART may preclude further neural injury.…”

Section: Introductionmentioning

confidence: 99%

Putamen volume and its clinical and neurological correlates in primary HIV infection

Wright

Ashmit

Vaida

et al. 2016

Aids

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Objective Little is known about the extent of cortical and subcortical volumetric alterations that may occur within the first year of HIV infection (primary HIV infection; PHI). Design We used structural MRI in this prospective cross-sectional neuroimaging study to determine the extent of volumetric changes in early HIV infection. Methods CSF, blood, NP testing, and structural T1 magnetic resonance imaging scans were acquired from 18 HIV- and 47 PHI age-matched, antiretroviral-naïve male participants. Using FreeSurfer 5.1, volumetric measurements were obtained from the caudate, amygdala, corpus callosum, ventricles, putamen, thalamus, cortical white matter, and total grey matter. Regional volumes were compared groupwise and related to biomarkers in cerebrospinal fluid (CSF) [viral load (VL), neopterin, and neurofilament light-chain (NFL)], blood (VL, CD4+, and CD8+ T cell count), and neuropsychometric tests [digit-symbol (DSST), grooved pegboard (GPD), finger-tapping (FT), and timed gait (TG)]. Results A trend-level moderate reduction of putamen volume (p=0.076, adjusted Cohen’s d=0.5 after controlling for age) was observed for PHI compared to HIV-uninfected individuals. Within the PHI group, putamen volume associated with CD4+ count (p=0.03), CD4+/CD8+ Ratio (p=0.045), infection duration (p=0.009), and worsening psychomotor performance on the DSST (p=0.028), FT (p=0.039), and TG (p=0.009) tests. Conclusions Our volumetric results suggest that the putamen is preferentially susceptible to early HIV-associated processes. Examining the natural course of early HIV infection longitudinally will allow for mapping of the trajectory of HIV-associated CNS changes, enabling creation of improved interventional strategies to potentially stabilize or reverse these observied structural changes.

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Brain alterations within the first 100 days of HIV infection

Cited by 90 publications

References 45 publications

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Diffusion Basis Spectral Imaging Detects Ongoing Brain Inflammation in Virologically Well-Controlled HIV+ Patients

Neuroinflammation-Induced Interactions between Protease-Activated Receptor 1 and Proprotein Convertases in HIV-Associated Neurocognitive Disorder

Putamen volume and its clinical and neurological correlates in primary HIV infection

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