Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND), cognitive impairment seen in approximately 50% of HIV+ patients, shares similar pathological hallmarks with Alzheimer’s disease (AD). Extracellular plaques composed of amyloid-beta (Aβ), which are produced by cleavage of amyloid precursor protein (APP) by the secretases BACE1, are observed in the brains of HAND. Aβ production is precluded by cleavage of APP by the non-amyloidogenic secretase ADAM10. BACE1 is increased in HAND as well as in our cell culture model of HIV neurotoxicity. Additionally, ADAM10 is decreased in response to excitotoxicity, a process crucial to HAND pathology, suggesting that there might be a shift in APP secretases contributing to HIV-mediated neurotoxicity. Therefore, understanding the mechanisms by which APP secretases are regulated is crucial in understanding and possibly developing therapies for HAND pathology. To address this, primary rat cortical neurons were treated with supernatants from HIV-infected human macrophages (HIV/MDMs). We found that HIV/MDMs decreased levels of both ADAM10 and Sirtuin1 (SIRT1), an enzyme shown to regulate ADAM10 levels, in primary neurons. Both ADAM10 and SIRT1 reductions were mediated through NMDA receptors. Furthermore, SIRT1 protein levels decreased earlier than ADAM10 and this early SIRT1 reduction was via proteasomal degradation. We also explored PKR-like Endoplasmic Reticulum Kinase (PERK), one of three effectors of the unfolded protein response (UPR), as a potential regulator of APP secretases as it has an established role in modulating BACE1. Using PERK inhibitors, we found that the ADAM10 decrease with HIV/MDMs was not through the PERK pathway. Interestingly, we found that a pharmacological PERK activator exacerbated HIV/MDM and NMDA-mediated decreases of ADAM10 as well as neurotoxicity. Activation of the PERK pathway in combination with other HIV-associated insults could contribute to neurotoxicity and Aβ production in HAND. This work reveals the mechanisms by which APP secretases are dysregulated in a cell culture model of HAND and provides new avenues for exploration.