Triumeq Increases Excitability of Pyramidal Neurons in the Medial Prefrontal Cortex by Facilitating Voltage-Gated Ca2+ Channel Function

Abstract

Combination antiretroviral therapy (cART) suppresses HIV-1 replication, improves immune function, and prolongs the life of people living with HIV (PLWH). However, cART also induces neurotoxicity that could complicate HIV-induced neurodegeneration while reduce its therapeutic efficacy in treating HIV/AIDS. Triumeq is a first-line cART regimen, which is co-formulated by three antiretroviral drugs (ARVs), lamivudine (3TC), abcavir (ABC), and dolutegravir (DTG). Little is known about potential side effects of ARVs on the brain (including those co-formulating Triumeq), and their mechanisms impacting neuronal activity. We assessed acute (in vitro) and chronic (in vivo) effects of Triumeq and co-formulating ARVs on pyramidal neurons in rat brain slices containing the medial prefrontal cortex (mPFC) using patch-clamp recording approaches. We found that acute Triumeq or 3TC in vitro significantly increased firing of mPFC neurons in a concentration- and time-dependent manner. This neuronal hyperactivity was associated with enhanced Ca2+ influx through voltage-gated Ca2+ channels (VGCCs). Additionally, chronic treatment with Triumeq in vivo for 4 weeks (4 wks) also significantly increased firing and Ca2+ influx via VGCCs in mPFC neurons, which was not shown after 2 wks treatment. Such mPFC neuronal hyperexcitability was not found after 4 weeks treatments of individual ARVs. Further, chronic Triumeq exposure in vivo significantly enhanced mRNA expression of low voltage-activated (LVA) L-type Ca2+ channels (Cav1.3 L-channels), while changes in high voltage-activated (HVA) Cav1.2 L-channels were not observed. Collectively, these novel findings demonstrate that chronic cART induces hyperexcitability of mPFC pyramidal neurons by abnormally promoting VGCC overactivation/overexpression of VGCCs (including, but may not limited to, LVA-Cav1.3 L-channels), which could complicate HIV-induced neurotoxicity, and ultimately may contribute to HIV-associated neurocognitive disorders (HAND) in PLWH. Determining additional target(s) of cART in mPFC pyramidal neurons may help to improve the therapeutic strategies by minimizing the side effects of cART for treating HIV/AIDS.

Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection

“…Consistent with this observation, we found a trend towards reduced medial orbitofrontal cortex in all groups, although the differences were only statistically significant in individuals who began cART later. While INSTI have been reported to induce neurotoxicity through several molecular mechanisms in in vitro studies, such as altering lysosomal function leading to neuroinflammation 41 or hyperexcitability of medial prefrontal cortex pyramidal neurons 42 , our data show that the longer-term effect of HIV-1 itself in the brain could be more harmful than potential INSTI-related neurotoxicity, at least to the extent that neuroimaging can reveal clinically significant findings.…”

Antiretroviral drugs from multiple classes induce loss of excitatory synapses between hippocampal neurons in culture

“…We found that co-application of Nim protected only against BIC-induced synapse loss, and this protection was incomplete. The finding that BIC-induced synapse loss has a VGCC component is interesting as the cART regimen Triumeq (DTG/ABC/3 TC) has been found to increase prefrontal pyramidal neuron excitability through low voltage activated L-type VGCCs, suggesting that as a class ISTIs might activate Ca 2+ channels ( Chen et al, 2020 ). Additionally, we assessed whether excessive glutamatergic signaling contributed to ARV-induced synapse loss as PIs have been shown to disrupt astrocytic excitatory amino acid transporter 2 expression and would thus elevate extracellular glutamate concentrations ( Vivithanaporn et al, 2016 ).…”

Editorial: Advances in Understanding NeuroHIV Associated Changes in Neuroimmune Communication in the Combined Anti-retroviral Therapy (cART) Era

“…Data suggest that neuroHIV stems, at least partially, from disruption of this communication, impairing neurotransmission, synapse formation/dissolution and neuroimmune communication. Some studies suggest that antiretroviral (ARV) drugs themselves may contribute to these changes in neuroimmune communication and neurological dysfunction (19)(20)(21)(22). The data from Tripathi et al support this possibility, showing that in both isolated rodent microglia and in HIV-1 transgenic rats, exposure to ART mediates microglial activation through oxidative stress-mediated lysosomal dysfunction.…”