Herpes Simplex Virus-1 in the Brain: The Dark Side of a Sneaky Infection

Herpes simplex virus-1 (HSV-1) establishes latency preferentially in sensory neurons of peripheral ganglia. A variety of stresses can induce recurrent reactivations of the virus, which spreads and then actively replicates to the site of primary infection (usually the lips or eyes). Viral particles produced following reactivation can also reach the brain, causing a rare but severe form of diffuse acute infection, namely herpes simplex encephalitis. Most of the time, this infection is clinically asymptomatic. However, it was recently correlated with the production and accumulation of neuropathological biomarkers of Alzheimer’s disease. In this review we discuss the different cellular and molecular mechanisms underlying the acute and long-term damage caused by HSV-1 infection in the brain. After primary infection, HSV-1 can reach the central nervous system where, in rare cases, it replicates and triggers an acute and inflammatory response resulting in herpes simplex encephalitis (HSE).The presence of the HSV-1 genome has been revealed in tissues of the peripheral and central nervous system of individuals with no clinical signs of HSE.In humans, levels of circulating anti-HSV immunoglobulins, considered as markers of HSV-1 reactivation, have been positively correlated with an increased risk of Alzheimer’s disease (AD).Experimental data show that HSV-1 infection of neurons activates neurotoxic pathways typical of AD, and repeated HSV-1 reactivations in the brain of infected mice produce an AD-like phenotype.Further studies are required to get greater mechanistic understanding of the causal links between recurrent HSV-1 infections in the brain and AD as well as to validate experimental findings in humans.