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.
Highlights
Combination antiretroviral therapy effectively suppresses HIV replication, improves immune function, and prolongs life of people living with HIV (PLWH), which transformed HIV infection from a fatal disease to a lifelong chronic, but manageable disease
It is worth noting that 1) the prefrontal cortex, hippocampus, and striatum are the key regulators of cognition; but they are most susceptible and vulnerable to HIV (Ferris et al, 2008; Manji et al, 2013; Hu, 2016); and (ii) neurotoxicity induced by antiretroviral drugs (ARVs) appears to be associated with dysregulation of neuronal Ca2+ homeostasis (Robertson et al, 2012; Romo et al, 2012; Akay et al, 2014; Apostolova et al, 2015; Underwood et al, 2015; Vivithanaporn et al, 2016), similar to that induced by HIV (Wayman et al, 2012, 2015, 2016; Napier et al, 2014; Khodr et al, 2016, 2018; Chen et al, 2019)
We found that voltage-sensitive Ca2+ influx through voltage-gated Ca2+ channel (VGCC) in medial prefrontal cortex (mPFC) pyramidal neurons was significantly enhanced by 3TC in a concentration-dependent manner (1, 4, 40 and 80 μM), evidenced by increased Ca2+ spike duration
Summary
Combination antiretroviral therapy (cART) effectively suppresses HIV replication, improves immune function, and prolongs life of people living with HIV (PLWH), which transformed HIV infection from a fatal disease to a lifelong chronic, but manageable disease. It is worth noting that 1) the prefrontal cortex, hippocampus, and striatum are the key regulators of cognition; but they are most susceptible and vulnerable to HIV (Ferris et al, 2008; Manji et al, 2013; Hu, 2016); and (ii) neurotoxicity induced by ARVs appears to be associated with dysregulation of neuronal Ca2+ homeostasis (i.e., excessive intracellular free calcium, [Ca2+]in) (Robertson et al, 2012; Romo et al, 2012; Akay et al, 2014; Apostolova et al, 2015; Underwood et al, 2015; Vivithanaporn et al, 2016), similar to that induced by HIV (Wayman et al, 2012, 2015, 2016; Napier et al, 2014; Khodr et al, 2016, 2018; Chen et al, 2019) These studies suggest that the site effects of cART disturb neuronal activity in the brain regions that regulate neurocognition, and indicate the necessity to elucidate the mechanism by which ARVs disrupt the brain function. We defined the mechanism (i.e., overactivation of VGCCs) by which Triumeq induces abnormal neuronal hyperactivity that may complicate HIV-induced neurotoxicity in the mPFC
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