Antiretroviral therapy administration reduces neuroinflammation without restoring brain-derived neurotrophic factor signaling in alcohol-administered simian immunodeficiency virus-infected macaques

Abstract

Objective: The present study examined interactions between simian immunodeficiency virus (SIV), chronic binge alcohol (CBA), and antiretroviral therapy (ART) on growth factor signaling, neuroinflammatory markers, viral loads (VL), and CD4 þ cell counts.Design: Adult male rhesus macaques were administered CBA (13-14 g ethanol (EtOH)/kg per week) or sucrose (SUC) 3 months prior to SIV mac251 infection until the study endpoint. At viral setpoint, a subset of CBA/SIVþ and SUC/SIVþ macaques were randomized to receive daily ART (9-[2-Phosphonyl-methoxypropyly]adenine [PMPA] 20 mg/kg, 2',3'-dideoxy-5-fluoro-3'-thiacytidine (FTC), 30 mg/kg). Frontal cortex (FC) and basal ganglia (BG) were collected for gene and protein expression.Methods: Relationships between brain and plasma VL or CD4 þ cell counts were determined using linear regression. Effects of SIV, CBA, and ART on markers of neuroinflammation and brain-derived neurotrophic factor (BDNF) signaling were determined by ANOVA and linear regression.Results: SIV increased FC and BG neuroinflammatory and glial cell gene expression (CX3CR1, B2M), and reduced FC protein kinase B phosphorylation. CBA decreased FC and BG tropomyosin receptor kinase B (TrkB) phosphorylation, and increased full-length TrkB (TrkB-FL) and SLC1A3 expression in FC and BG, respectively. ART suppressed plasma and brain VL, reduced neuroinflammatory gene expression in FC (IBA1, CX3CR1, and GFAP), and BG (CD74 and CD11ß), and did not restore FC or BG BDNF signaling deficits.Conclusions: Results show ART-mediated reduction in VL and neuroinflammatory gene expression, irrespective of CBA administration. ART did not attenuate SIV-and CBA-mediated BDNF signaling deficits, suggesting these deficits, despite effective neuroinflammation suppression, may explain CBA-and SIV-associated neurocognitive deficits. Therapeutics targeting growth factor signaling may be important adjuvants in treating HIV-associated neurocognitive decline.

Porcine alveolar macrophages host proteins interacting with African swine fever virus p72

“…p72 has multiple antigenic neutralization epitopes and can be neutralized and blocked by p72 antibodies, playing an important role in the immune response ( Zsak et al, 1993 ; Miao et al, 2023 ). Proteomic data analysis revealed that after ASFV infection of PAMs, the expression of B2M, an important peptide recognition and presentation protein, was significantly upregulated, consistent with the phenomenon caused by simian immunodeficiency virus and human immunodeficiency virus infections ( Chitra et al, 2011 ; Maxi et al, 2021 ). Therefore, we speculated that this protein plays an important immune function in the infection process, and that the interaction between p72 and B2M may affect this process.…”

HIV on the brain: is neurosignalling damage irreversible even on antiretroviral therapy?

“…The reduction of BDNF in PWH who abuse alcohol is most likely a consequence of both viral infection induced neuroinflammation and alcohol-related neurosignal suppression. Due to this multifactorial causation, treatment of the virus alone may not be enough, as shown in the current study by Maxi et al [5]. In addition to prescribing physical exercises to increase BDNF levels in the brain [13], there are a number of drugs that modulate BDNF signalling, including several antidepressants and small molecule mimetic of BDNF such 7,8-DHF and P021 [14,15].…”

“…In this issue, a new study by Maxi et al [5] uses a simian immunodeficiency virus (SIV)-infected rhesus macaque model wherein they study the effects of infection as well as binge alcohol use on measures of neuroinflammation. The investigators further evaluate the impact of ART in this model to reduce inflammation and restore neurosignals.…”

“…Given the difficulties of sampling the brain in humans, nonhuman primate (NHP) infected with lentivirus offers an opportunity to determine this. In this new study, Maxi et al [5] started dosing NHP with alcohol 3 months prior to SIV infection and continued through the end of the study, while ART was given 2.5 months after infection and tissues obtain 11 months after infection. Although this study timeline modelled the most likely sequences of exposures in human, longitudinal studies with CNS samplings at multiple time points could further elaborate the findings.…”