Characterization of a doxycycline inducible and astrocyte-specific HIV-1 Nef transgenic mouse model (iNef)

Purpose: Over 37 million people worldwide are currently infected with human immunodeficiency virus type 1 (HIV-1). Introduction of combination antiretroviral therapy has improved the quality and length of life, leading to increased incidents of minor cognitive and motor disorder. HIV-1 infects astrocytes, the most abundant cells of the central nervous system (CNS). Once infected, astrocytes become reactive, characterized by increased expression of astrocyte-specific protein glial fibrillary acidic protein (GFAP). However, those cells do not support productive HIV replication, primarily expressing non-structural viral proteins, such as Tat and Nef. Although the role of Tat in HIV/neuroAIDS has been extensively studied, little is known about the roles of Nef in HIV/NeuroAIDS. Nef is known to play important roles in immune evasion, T-cell depletion, and disease progression. The current study is to characterize roles of Nef in HIV/neuroAIDS. Method: A doxycycline inducible astrocyte-specific HIV-1 Nef transgenic mouse model (iNef) was created. In this model, Nef expression is under the control of both GFAP promoter and doxycycline responsive elements, which allows characterization of the effects of Nef expression on the CNS, independent of HIV-1 infection. Neuropathological outcomes (astrocytosis, neuroinflammation, and neuronal integrity) and neurobehavioral effects (motor and memory) were determined using immunofluorescence staining and neurobehavioral batteries, respectively. Results: Nef expression was confirmed in the brain of the iNef mice with doxycycline induction. Meanwhile, Increased GFAP expression and cytokine expression, loss of neuronal dendrites and decreased speed and latency to fall were found in these Nef-expressing iNef mice. Conclusion: These data show that Nef expression led to astrocytosis, neuroinflammation, compromised neuronal integrity, and impaired coordination and motor function in Nef-expressing iNef mice and suggest that Nef could be a major contributing factor to HIV/neuroAIDS. Further investigation is under way to determine the underlying molecular mechanisms.