Decoding T Cell Responses to Herpes Simplex Virus Infection in Skin Using Highly Multiplexed Tissue Imaging

Abstract

Herpes Simplex Virus (HSV) is a prevalent global health concern, with two main subtypes, HSV-1 and HSV-2, infecting billions of people. While HSV-1 typically causes cold sores and HSV-2 is associated with genital herpes, both can manifest in various forms. Infections often result in painful lesions, but many remain asymptomatic. Immunocompromised individuals face severe complications, including increased susceptibility to HIV infection. HSV establishes latency in neurons, periodically reactivating to cause viral shedding. Most reactivations are subclinical, contributing to the high global prevalence of HSV. Despite ongoing research, there is no cure or vaccine available. T cells play a crucial role in controlling HSV infections, with tissue-resident memory cells (TRMs) influencing reactivation frequency. Chronic infections can lead to T cell exhaustion, characterized by diminished effector functions and memory T cell development, leading to an inadequate immune response. Our study examined T cell responses in HSV-infected skin, exploring activation, exhaustion, regulation, and survival during lesion healing. Using advanced imaging and machine learning techniques, we observed a shift from activated T cells to TRMs post-healing. Additionally, regulatory T cell density was elevated in patients with higher shedding rates. Currently, there is no vaccine available to prevent HSV infection and transmission. However, a deeper understanding of T cell dynamics during lesion healing has the potential to directly guide vaccine development efforts aimed at leveraging T cell responses for effective prevention.