The TH1/TH2 Response Imbalance Zika Virus Pathogenesis: An Immunological Paradox

Since its identification in 1947 and its global emergence in the Americas decades later, the Zika virus (ZIKV) has proven to be a multifaceted challenge to public health. Among the many aspects that remain poorly understood, the complex immunological paradox between Th1 and Th2 responses stands out, playing a central role in the immunopathogenesis of the infection. This narrative review critically explores how scientific literature has addressed this duality, highlighting that an exacerbated Th1 response-although effective in viral containment-is frequently associated with severe outcomes, such as heightened inflammation and autoimmune manifestations, including Guillain-Barré syndrome. Conversely, a predominant Th2 profile, generally linked to milder clinical presentations, may favor viral persistence and, paradoxically, contribute to late-onset neurological complications, such as encephalitis. Additionally, we discuss the central role of interactions between CD4⁺ and CD8⁺ T cells, monocytes, NK cells, and B cells, which, although essential for immune control of the infection, may, when dysregulated, exacerbate pathogenesis. By unraveling the mechanisms behind this delicate balance between antiviral defense and immune-mediated damage, we aim to shed light on new therapeutic perspectives. Understanding the nature and consequences of this Th1/Th2 paradox is crucial for guiding the development of immunomodulatory strategies that foster an effective response against ZIKV, while minimizing the risk of neurological injury.