HIV Tat causes synapse loss in a mouse model of HIV‐associated neurocognitive disorder that is independent of the classical complement cascade component C1q

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Abstract
Microglial activation, increased proinflammatory cytokine production, and a reduction in synaptic density are key pathological features associated with HIV‐associated neurocognitive disorders (HAND). Even with combination antiretroviral therapy (cART), more than 50% of HIV‐positive individuals experience some type of cognitive impairment. Although viral replication is inhibited by cART, HIV proteins such as Tat are still produced within the nervous system that are neurotoxic, involved in synapse elimination, and provoke enduring neuroinflammation. As complement deposition on synapses followed by microglial engulfment has been shown during normal development and disease to be a mechanism for pruning synapses, we have tested whether complement is required for the loss of synapses that occurs after a cortical Tat injection mouse model of HAND. In Tat‐injected animals evaluated 7 or 28 days after injection, levels of early complement pathway components, C1q and C3, are significantly elevated and associated with microgliosis and a loss of synapses. However, C1qa knockout mice have the same level of Tat‐induced synapse loss as wild‐type (WT) mice, showing that the C1q‐initiated classical complement cascade is not driving synapse removal during HIV1 Tat‐induced neuroinflammation.
Funding Information
  • National Institute of Allergy and Infectious Diseases (P30 AI078498)
  • National Institute of Mental Health (F32 MH105288, P01 MH064570, R01 MH104147)

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