Improved Cognitive Performance and Reduced Monocyte Activation in Virally Suppressed Chronic HIV After Dual CCR2 and CCR5 Antagonism

D’Antoni, Michelle L; Paul, Robert; Mitchell, Brooks I.; Kohorn, Lindsay; Fischer, Laurent; Lefebvre, E.; Seyedkazemi, Star; Nakamoto, Beau K.; Walker, Maegen; Kallianpur, Kalpana J.; Ogata‐Arakaki, Debra; Ndhlovu, Lishomwa C.; Shikuma, Cecilia

doi:10.1097/qai.0000000000001752

Cited by 50 publications

(31 citation statements)

References 59 publications

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“…Further evidence for the dual role of CCL2 in HIV comes from findings in individuals with genetic variants that promote CCL2 expression whereby carriers of this variant are at a lower risk of acquiring HIV‐1; however, once infected, the same genetic variant promotes monocyte infiltration, increases risk for HIV‐associated dementia (Gonzalez et al, ), and is associated with increased levels of pro‐inflammatory molecules in CSF (Thames et al, ). Relevant to our findings, a recent clinical trial of virologically‐suppressed patients treated with cenicriviroc, a dual CCR2/CCR5 chemokine receptor antagonist, revealed an improvement in cognitive performance (D'Antoni et al, ). Cenicriviroc has been shown to be effective in reducing transmigration of monocytes, and as such may be useful in reducing infiltration of infected monocytes into the CNS (Veenstra et al, ).…”

Section: Discussionsupporting

confidence: 84%

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: 84%

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 findings concur with the enhanced freezing responses to the context reported in CFC-trained mice lacking CX3CR1 (transgenic mice lacking this delta chemokine receptor) [44]. Moreover, the enhanced fear memory in maraviroc CFC-trained rats agrees with the improved cognitive responses of viral-suppressed chronic HIV seropositive patients (suppressed viral load) following CCR5 antagonism by maraviroc [43]. Maraviroc crosses the blood-brain barrier and it specifically blocks CCR5 but not CCR1 [45].…”

Section: Discussionsupporting

confidence: 82%

“…Chemokines contribute neural-activity-dependent changes and PSA-NCAM (polysialylated-cell adhesion molecule) also contributes to traumatic memory consolidation in rats [26,28,29,42]. As dendrite-selective redistribution of chemokine receptors (i.e, CXCR4) has been observed following agonist stimulation [43], these RANTES elevations could promote neuroplastic changes via CCR5 during traumatic memory (fear memory) consolidation. Maraviroc (a CCR5 antagonist) treatment before fear learning increased corticosterone levels and also enhanced fear memory consolidation (to the context) at 24 h after the CFC session as compared to vehicle CFC-trained rats.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal CCR5/RANTES Elevations in a Rodent Model of Post-Traumatic Stress Disorder: Maraviroc (a CCR5 Antagonist) Increases Corticosterone Levels and Enhances Fear Memory Consolidation

Merino

Muñetón-Gómez

et al. 2020

Biomolecules

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Background: Contextual fear conditioning (CFC) is a rodent model that induces a high and long-lasting level of conditioning associated with traumatic memory formation; this behavioral paradigm resembles many characteristics of posttraumatic stress disorder (PSTD). Chemokines (chemotactic cytokines) play a known role in neuronal migration and neurodegeneration but their role in cognition is not totally elucidated. Aim: We ascertain whether CCR5/RANTES beta chemokines (hippocampus/prefrontal cortex) could play a role in fear memory consolidation (CFC paradigm). We also evaluated whether chronic stress restraint (21 days of restraint, 6-h/day) could regulate levels of these beta chemokines in CFC-trained rats; fear memory retention was determined taking the level of freezing (context and tone) by the animals as an index of fear memory consolidation 24 h after CFC training session; these chemokines (CCR5/RANTES) and IL-6 levels were measured in the hippocampus and prefrontal cortex of chronically stressed rats, 24 h after CFC post-training, and compared with undisturbed CFC-trained rats (Experiment 1). In Experiment 2, rats received 1 mA of footshock during the CFC training session and fear memory consolidation was evaluated at 12 and 24 h after CFC training sessions. We evaluated whether RANTES levels could be differentially regulated at 12 and 24 h after CFC training; in Experiment 3, maraviroc was administered to rats (i.m: 100 mg/Kg, a CCR5 antagonist) before CFC training. These rats were not subjected to chronic stress restraint. We evaluated whether CCR5 blockade before CFC training could increase corticosterone, RANTES, or IL-6 levels and affects fear memory consolidation in the rats 24-h post-testing compared with vehicle CFC-trained rats. Results: Elevations of CCR5/RANTES chemokine levels in the hippocampus could have contributed to fear memory consolidation (24 h post-training) and chronic stress restraint did not affect these chemokines in the hippocampus; there were no significant differences in CCR5/RANTES levels between stressed and control rats in the prefrontal cortex (Experiment 1). In Experiment 2, hippocampal CCR5/RANTES levels increased and enhanced fear memory consolidation was observed 12 and 24 h after CFC training sessions with 1 mA of footshock. Increased corticosterone and CCR5/RANTES levels, as well as a higher freezing percentage to the context, were found at 24 h CFC post-testing in maraviroc-treated rats as compared to vehicle-treated animals (experiment-3). Conversely, IL-6 is not affected by maraviroc treatment in CFC training. Conclusion. Our findings suggest a role for a hippocampal CCR5/RANTES axis in contextual fear memory consolidation; in fact, RANTES levels increased at 12 and 24 h after CFC training. When CCR5 was blocked by maraviroc before CFC training, RANTES (hippocampus), corticosterone levels, and fear memory consolidation were greater than in vehicle CFC-trained rats 24 h after the CFC session.

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“…Given that HIV and CVD are complex pathologies in which several chemokine/CKR axes contribute to disease, targeting multiple CKRs may ultimately yield better disease outcome. In support of this, we found in a new single arm open‐label trial in virally suppressed HIV‐infected adults on stable ART, CVC intensification improved neuropsychological testing performance and reduced monocyte activation (in press) . Overall our trans‐endothelial migration study highlights the potential antiatherosclerotic effects of CVC, in both HIV and non‐HIV settings, by potentially limiting monocyte/macrophage inflammation and decreasing monocyte infiltration into atherosclerotic plaques.…”

Section: Discussionsupporting

confidence: 73%

Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

D’Antoni

Mitchell

McCurdy

et al. 2018

Journal of Leukocyte Biology

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Incidences of cardiovascular diseases (CVD) are high among virologically suppressed HIV-infected individuals. Monocyte activation and trafficking are key mechanisms in the evolution of CVD. We studied the ability of cenicriviroc (CVC), a dual C-C chemokine receptor type 2 (CCR2) and CCR5 antagonist, to influence the migration of monocytes from HIV-infected individuals on antiretroviral therapy (ART). Monocytes were derived from 23 ART-suppressed HIV-infected and 16 HIV-uninfected donors. In a trans-endothelial migration model, monocytes, and human aortic endothelial cells (HAoECs) were exposed to cenicriviroc and migrated monocytes, quantified. Expression of CCR2 and CCR5 on monocytes and adhesion molecules (E-selectin, ICAM-1, VCAM-1, PECAM-1, and CD99) on HAoECs were measured. The single antagonists, BMS-22 (CCR2), and maraviroc (CCR5), served as controls. When both HAoECs and monocytes together were exposed to the antagonists, cenicriviroc led to a greater decrease in monocyte migration compared to BMS-22 or vehicle in both HIV-infected and HIV-uninfected groups (P < 0.05), with maraviroc having no inhibitory effect. Cenicriviroc treatment of HAoECs alone decreased monocyte migration in the HIV-infected group when compared to vehicle (P < 0.01). Inhibition of migration was not evident when monocytes alone were exposed to cenicriviroc, BMS-22 or maraviroc. Incubation of HAoECs with cenicriviroc decreased E-selectin expression (P = 0.045) but had limited effects on the other adhesion molecules. Cenicriviroc inhibits monocyte trans-endothelial migration more effectively than single chemokine receptor blockade, which may be mediated via disruption of monocyte-endothelial tethering through reduced E-selectin expression. Cenicriviroc should be considered as a therapeutic intervention to reduce detrimental monocyte trafficking.

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Improved Cognitive Performance and Reduced Monocyte Activation in Virally Suppressed Chronic HIV After Dual CCR2 and CCR5 Antagonism

Cited by 50 publications

References 59 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

Hippocampal CCR5/RANTES Elevations in a Rodent Model of Post-Traumatic Stress Disorder: Maraviroc (a CCR5 Antagonist) Increases Corticosterone Levels and Enhances Fear Memory Consolidation

Cenicriviroc inhibits trans-endothelial passage of monocytes and is associated with impaired E-selectin expression

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