Nef mediates neuroimmune response, myelin impairment, and neuronal injury in EcoHIV-infected mice.

The introduction of antiretroviral therapy has markedly improved the management of HIV-associated neurocognitive disorders (HAND). However, HAND still affects nearly half of HIV-infected individuals, presenting significant challenges to their well-being. This highlights the critical need for a deeper understanding of HAND mechanisms. Among HIV viral proteins, Nef is notable for its multifaceted role in HIV pathogenesis, though its specific involvement in HAND remains unclear. To investigate this, we used a murine model infected with Nef-expressing (EcoHIV) and Nef-deficient (EcoHIVΔNef) murine HIV. Comparative analyses revealed increased neuroinflammation and reduced myelin and neuronal integrity in EcoHIV-infected brains compared with those with EcoHIVΔNef. Both viruses induced astrogliosis, with stronger GFAP activation in Nef-deficient infections. These findings suggest that Nef contributes to neuroinflammation, primarily through microglial targeting and demyelination, although other factors may regulate astrogliosis. Our results indicate that Nef may significantly contribute to neuronal injury in EcoHIV-infected mice, offering insights into Nef-induced neuropathology in HAND and guiding future research.