The prevalence of Alzheimer's disease (AD) and the hyperphosphorylation of the microtubule-associated protein tau, a key biomarker of AD, are known to be increased in HIV patients. Much is unclear regarding the molecular mechanisms of how HIV infection triggers AD onset, but the hyperexcitation of neurons, which leads to their damage, is likely an important step. The team of Seonil Kim has previously shown that the HIV glycoprotein gp120 and the feline immunodeficiency virus (FIV) glycoprotein gp95 induce synaptic hyperexcitation via activation of cGMP-dependent protein kinase II (cGKII). Now, in a new study (Sathler et al., 2022), they investigate a possible link between this mechanism and cellular tau pathology. Using cultured mouse cortical neurons, they show that HIV gp120 and FIV gp95 are sufficient to increase extracellular tau concentration via cGKII-dependent neuronal hyperexcitation. Importantly, in addition to extracellular tau release, cGKII activation triggered by these glycoproteins also leads to tau hyperphosphorylation. Finally, the authors demonstrate that during this process, cGKII is activated by the kinase p38. Taken together, the findings of this study provide an important connection between HIV infection and tau pathologies, and will inform future studies that aim to develop treatments for HIV patients suffering from early-onset AD.