Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

Imp, Brandon; Rubin, Leah H.; Tien, Phyllis C.; Plankey, Michael; Golub, Elizabeth T.; French, Audrey L.; Valcour, Victor

doi:10.1093/infdis/jiw506

Cited by 73 publications

(50 citation statements)

References 44 publications

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“…Elevated blood levels of monocyte activation markers are correlated with worse cognitive performance in HIV‐infected individuals despite suppression of plasma HIV RNA. This evidence supports the notion that impaired cognition may be a consequence of other factors beyond viral replication (Imp et al, ).…”

Section: Discussionsupporting

confidence: 87%

HIV‐1 Tat promotes astrocytic release of CCL2 through MMP/PAR‐1 signaling

Bozzelli

Yin

Avdoshina

et al. 2019

Glia

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The HIV‐1 protein Tat is continually released by HIV‐infected cells despite effective combination antiretroviral therapies (cART). Tat promotes neurotoxicity through enhanced expression of proinflammatory molecules from resident and infiltrating immune cells. These molecules include matrix metalloproteinases (MMPs), which are pathologically elevated in HIV, and are known to drive central nervous system (CNS) injury in varied disease settings. A subset of MMPs can activate G‐protein coupled protease‐activated receptor 1 (PAR‐1), a receptor that is highly expressed on astrocytes. Although PAR‐1 expression is increased in HIV‐associated neurocognitive disorder (HAND), its role in HAND pathogenesis remains understudied. Herein, we explored Tat's ability to induce expression of the PAR‐1 agonists MMP‐3 and MMP‐13. We also investigated MMP/PAR‐1‐mediated release of CCL2, a chemokine that drives CNS entry of HIV infected monocytes and remains a significant correlate of cognitive dysfunction in the era of cART. Tat exposure significantly increased the expression of MMP‐3 and MMP‐13. These PAR‐1 agonists both stimulated the release of astrocytic CCL2, and both genetic knock‐out and pharmacological inhibition of PAR‐1 reduced CCL2 release. Moreover, in HIV‐infected post‐mortem brain tissue, within‐sample analyses revealed a correlation between levels of PAR‐1‐activating MMPs, PAR‐1, and CCL2. Collectively, these findings identify MMP/PAR‐1 signaling to be involved in the release of CCL2, which may underlie Tat‐induced neuroinflammation.

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Section: Discussionsupporting

confidence: 87%

HIV‐1 Tat promotes astrocytic release of CCL2 through MMP/PAR‐1 signaling

Bozzelli

Yin

Avdoshina

et al. 2019

Glia

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“…10 Other groups document persistent monocyte activation as measured by soluble CD163 in plasma linked to poor cognitive performance despite plasma viral suppression. 40,41 …”

Section: Discussionmentioning

confidence: 99%

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years

Clifford

Samboju

Cobigo

et al. 2017

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background Current HIV treatments are successful at suppressing plasma HIV RNA to undetectable levels for most adherent patients. Yet, emerging evidence suggests viral suppression will inadequately control inflammation and mitigate risk for progressive brain injury. We sought to quantify differences in longitudinal brain atrophy rates among older virally suppressed HIV-infected participants compared to that of healthy aging. Methods We examined longitudinal structural brain MRI atrophy rates employing region of interest assessments and voxel-wise tensor-based morphometry in HIV-infected participants over age 60 years (n=38) compared to age-matched HIV-uninfected healthy and cognitively normal controls (n=24). Results The mean age of participants was 63 years, the mean estimated duration of infection was 21 years and the median of duration of documented viral suppression was 3.2 years. Average proximal and nadir CD4 counts were 550 and 166, respectively; 15/38 (39%) met criteria for HIV-associated neurocognitive disorder. In models adjusting for age and sex, HIV serostatus was associated with more rapid average annualized rates of atrophy in the cerebellum (0.42% vs. 0.02%, p=0.016), caudate (0.74% vs. 0.03%, p=0.012), frontal lobe (0.48% vs. 0.01%, p=0.034), total cortical gray matter (0.65% vs. 0.16%, p=0.027), brain stem (0.31% vs. 0.01%, p=0.026), and pallidum (0.73% vs. 0.39%, p=0.046). Among those with HIV, atrophy rates did not differ statistically by cognitive status. Conclusion Despite persistent control of plasma viremia, these older HIV-infected participants demonstrate more rapid progressive brain atrophy when compared to healthy aging. Either HIV or other factors that differ between older HIV-infected participants and healthy controls could be responsible for these differences.

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“…Most likely we are examining prevalent and not incident cases of CI. No peripheral monocyte-driven immune activation markers such as soluble CD163 and CD14 were studied but have shown associations with CI (Burdo et al , 2013b; Royal et al , 2016) including in the WIHS (Imp et al , 2017). While the use of propensity matching yielded four groups that were balanced on a number of sociodemographic, clinical, and behavioural characteristics know to be associated with cognitive impairment, this approach controls only for measured confounders and unmeasured factors can still bias results.…”

Section: Discussionmentioning

confidence: 99%

Variability in C-reactive protein is associated with cognitive impairment in women living with and without HIV: a longitudinal study

et al. 2017

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Despite the availability of effective antiretroviral therapies, cognitive impairment (CI) remains prevalent in HIV-infected (HIV+) individuals. Evidence from primarily cross-sectional studies, in predominantly male samples implicates monocyte and macrophage-driven inflammatory processes linked to HIV-associated CI. Thus, peripheral systemic inflammatory markers may be clinically useful biomarkers in tracking HIV-associated CI. Given sex differences in immune function, we focused here on whether mean and intraindividual variability in inflammatory markers predicted CI in HIV+ and HIV− women. Seventy-two HIV+ (36 with CI) and 58 HIV− (29 with CI) propensity-matched women participating in the Women’s Interagency HIV Study completed a neuropsychological battery once between 2009–2011 and performance was used to determine CI status. Analysis of 13 peripheral immune markers was conducted on stored biospecimens at 3 time points (7 and 3.5 years before neuropsychological data collection and concurrent with data collection). HIV+ women showed alterations in 8 immune markers compared to HIV− women. The strongest predictors of CI across HIV+ and HIV− women were lower mean soluble tumor necrosis factor receptor I (sTNFRI) levels, higher mean interleukin (IL)-6 levels, and greater variability in C-reactive protein (CRP) and matrix metalloproteinase (MMP)-9 (p’s<0.05). Stratified by HIV, the only significant predictor of CI was greater variability in CRP for both HIV+ and HIV− women (p’s<0.05). This variability predicted lower executive function, attention/working memory, and psychomotor speed in HIV+ but only learning in HIV− women (p’s<0.05). Intraindividual variability in CRP levels over time may be a good predictor of CI in predominately minority low socioeconomic status midlife women.

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Monocyte Activation Is Associated With Worse Cognitive Performance in HIV-Infected Women With Virologic Suppression

Cited by 73 publications

References 44 publications

HIV‐1 Tat promotes astrocytic release of CCL2 through MMP/PAR‐1 signaling

HIV‐1 Tat promotes astrocytic release of CCL2 through MMP/PAR‐1 signaling

Progressive Brain Atrophy Despite Persistent Viral Suppression in HIV Patients Older Than 60 Years

Variability in C-reactive protein is associated with cognitive impairment in women living with and without HIV: a longitudinal study

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