Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca²⁺ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca²⁺ activity using intracellular Ca²⁺ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca²⁺ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca²⁺ by the activation of the endoplasmic reticulum (ER)-associated Ca²⁺ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95’s stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca²⁺ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca²⁺ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca²⁺ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND. Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HANDs) occur in as many as 50% of individuals infected with HIV, including patients receiving combination antiretroviral therapy (cART). Notably, while neuronal death is mitigated with cART, neuronal dysfunction persists. This study investigates HAND-associated alteration of neuronal function, in particular, synaptic activity. The development of therapies designed to prevent HAND requires a detailed understanding of pathogenic mechanisms—processes difficult to study in humans. Here, we develop a feline immunodeficiency virus (FIV) model to study this question. FIV is genetically and functionally similar to HIV and produces a naturally occurring AIDS that is frequently associated with the development of neurological disease. We demonstrate that FIV and HIV share the core cellular pathway that alters neuronal activity via aberrant neuronal activation of cGMP-dependent protein kinase II. Thus, FIV infection of cats can be a valuable model to investigate the neurobiological mechanisms of HAND-associated neuropathogenesis.

The vertebrate embryonic heart initially forms with two chambers, a ventricle and an atrium, separated by the atrioventricular junction. Localized genetic and biomechanical information guides the development of valves, which function to ensure unidirectional blood flow. If the valve development process goes awry, pathology associated with congenital valve defects can ensue. Congenital valve defects (CVD) are estimated to affect 1–2% of the population and can often require a lifetime of treatment. Despite significant clinical interest, molecular genetic mechanisms that direct valve development remain incompletely elucidated. Cells in the developing valve must contend with a dynamic hemodynamic environment. A growing body of research supports the idea that cells in the valve are highly sensitive to biomechanical forces, which cue changes in gene expression required for normal development or for maintenance of the adult valve. This review will focus on mechanotransductive pathways involved in valve development across model species. We highlight current knowledge regarding how cells sense physical forces associated with blood flow and pressure in the forming heart, and summarize how these changes are transduced into genetic and developmental responses. Lastly, we provide perspectives on how altered biomechanical cues may lead to CVD pathogenesis.

Heart valve development is governed by both genetic and biomechanical inputs. Prior work has demonstrated that oscillating shear stress associated with blood flow is required for normal atrioventricular (AV) valve development. Cardiac afterload is defined as the pressure the ventricle must overcome in order to pump blood throughout the circulatory system. In human patients, conditions of high afterload can cause valve pathology. Whether high afterload adversely affects embryonic valve development remains poorly understood. Here we describe a zebrafish model exhibiting increased myocardial afterload, caused by vasopressin, a vasoconstrictive drug. We show that the application of vasopressin reliably produces an increase in afterload without directly acting on cardiac tissue in zebrafish embryos. We have found that increased afterload alters the rate of growth of the cardiac chambers and causes remodeling of cardiomyocytes. Consistent with pathology seen in patients with clinically high afterload, we see defects in both the form and the function of the valve leaflets. Our results suggest that valve defects are due to changes in atrioventricular myocyte signaling, rather than pressure directly acting on the endothelial valve leaflet cells. Cardiac afterload should therefore be considered a biomechanical factor that particularly impacts embryonic valve development.