Unravelling the Viral Hypothesis of Schizophrenia: A Comprehensive Review of Mechanisms and Evidence

Abstract

Schizophrenia is a challenging multifactorial neuropsychiatric disease that involves interactions between genetic susceptibility and environmental insults. Increasing evidence implicates viral infections as significant environmental contributors, particularly during sensitive neurodevelopmental periods. This review synthesises current findings on the viral hypothesis of schizophrenia, encompassing a wide array of neurotropic viruses, including influenza viruses, herpesviruses (HSV-1 and 2, CMV, VZV, EBV, HHV-6 and 8), hepatitis B and C viruses, HIV, HERVs, HTLV, Zika virus, BoDV, coronaviruses (including SARS-CoV-2), and others. These pathogens can contribute to schizophrenia through mechanisms such as direct microinvasion, persistent central nervous system infection, immune-mediated neuroinflammation, molecular mimicry, and the disturbance of the blood-brain barrier. Prenatal exposure to viral infections can trigger maternal immune activation, resulting in cytokine-mediated alterations in the neurological development of the foetus that persist into adulthood. Genetic studies highlight the role of immune-related loci, including major histocompatibility complex polymorphisms, in modulating susceptibility to infection and neurodevelopmental outcomes. Clinical data also support the "mild encephalitis" hypothesis, suggesting that a subset of schizophrenia cases involve low-grade chronic neuroinflammation. Although antipsychotics have some immunomodulatory effects, adjunctive anti-inflammatory therapies show promise, particularly in treatment-resistant cases. Despite compelling associations, pathogen-specific links remain inconsistent, emphasising the need for longitudinal studies and integrative approaches such as viromics to unravel causal relationships. This review supports a "multi-hit" model in which viral infections interfere with hereditary and immunological susceptibilities, enhancing schizophrenia risk. Elucidating these virus-immune-brain interactions may facilitate the discovery of biomarkers, targeted prevention, and novel therapeutic strategies for schizophrenia.

Keywords: herpesviruses; immunogenetics; maternal immune activation; neuroinflammation; schizophrenia; viral infections; viromics.

Figure 1

Neurotropic and systemic viruses implicated in the aetiopathogenesis of schizophrenia. HSV 1, 2: herpes simplex virus types 1 and 2; HHV 6, 8: human herpesviruses 6 and 8; EBV: Epstein–Barr virus; CMV: cytomegalovirus; HIV: human immunodeficiency virus; HCV: hepatitis C virus; HBV: hepatitis B virus; VZV: varicella-zoster virus; BoDV: Borna disease virus; ZIKV: Zika virus; HERV: human endogenous retrovirus.

Figure 2

Hypothesized pathogenic pathways linking VZV infection to schizophrenia. VZV: varicella-zoster virus. IFN-γ: interferon-gamma. LAT: latency-associated transcript. MiRNAs: microRNAs. ORF63: open reading frame 63; (): inhibition.

Figure 3

Mechanistic insights into HHV-8 involvement in the aetiopathogenesis of schizophrenia. HHV-8: human herpesvirus-8; vIL-6: viral interleukin-6; hIL-6: human interleukin-6; Th1: T-helper type 1 lymphocyte; Th2: T-helper type 2 lymphocyte; (↑): stimulation; (↓): induction.

Figure 4

Pathophysiological pathways implicating hepatitis C virus in development of schizophrenia. CNS: central nervous system; HCV: hepatitis C virus; BMVECs: brain microvascular endothelial cells; BBB: blood–brain barrier; QUIN: quinolinic acid.

Figure 5

Immunopathological and neurobiological mechanisms connecting HIV and schizophrenia. HIV: human immunodeficiency virus; BBB: blood–brain barrier; LLNI: low-level neuroinflammation; KYNA: kynurenic acid; NMDA: N-methyl-D-aspartate receptor; (+): stimulation; (−): inhibition; (↓): reduction; (↑): increase.

Figure 6

Neuropsychiatric sequelae of COVID-19.

Figure 7

Other viral contributors to schizophrenia. HTLV: human T cell leukaemia virus.