Herpes simplex virus (HSV) pathogenesis in humans

HSV-2 is a leading cause of genital ulcer disease and a risk factor for HIV acquisition and transmission. In human HSV-2 infection, the disease spectrum varies widely: from completely asymptomatic, to infrequent and short-lasting recurrences, to frequent and severe genital ulcerations. Recent studies have shown that over 80% of HSV-2 reactivations are subclinical and of short duration. This indicates that a rapid host immune response in the genital skin and mucosa can contain viral reactivation, preventing symptoms. Through analyzing the cellular immune infiltrates of HSV-2 lesions from patients on and off antiviral therapy, we have discovered that CD4+ and CD8+ T cells, along with various populations of dendritic cells, form an immune milieu in the genitalia. This milieu provides enriched target cells that are positive for HIV receptor expression, even with daily antiviral therapy. Ongoing research in the lab seeks to further characterize HSV-2 pathogenesis using “state-of-the-art” in situ technologies and novel in vitro platforms to identify key factors the contribute to viral control.

Publications

Zhu J, Koelle DM, Cao J, Vazquez J, Huang ML, Hladik F, Wald A, Corey L. Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation. J Exp Med. 2007 Mar 19;204(3):595-603. 

Zhu J, Hladik F, Woodward A, Klock A, Peng T, Johnston C, Remington M, Magaret A, Koelle DM, Wald A, Corey L. Persistence of HIV-1 receptor-positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisition. Nat Med. 2009 Aug;15(8):886-92. doi: 10.1038/nm.2006. Epub 2009 Aug 2. PMID: 19648930; PMCID: PMC2723183.    

Milman N, Zhu J, Johnston C, Cheng A, Magaret A, Koelle DM, Huang ML, Jin L, Klock A, Layton ED, Corey L. In Situ Detection of Regulatory T Cells in Human Genital Herpes Simplex Virus Type 2 (HSV-2) Reactivation and Their Influence on Spontaneous HSV-2 Reactivation. J Infect Dis. 2016 Jul 1;214(1):23-31.

Lo M, Zhu J, Hansen SG, Carroll T, Farr Zuend C, Nöel-Romas L, Ma ZM, Fritts L, Huang ML, Sun S, Huang Y, Koelle DM, Picker LJ, Burgener A, Corey L, Miller CJ. Acute Infection and Subsequent Subclinical Reactivation of Herpes Simplex Virus 2 after Vaginal Inoculation of Rhesus Macaques. J Virol. 2019 Jan 4;93(2):e01574-18.

Tissue-resident-memory CD8+ T cell function and regulation in human skin

Tissue resident memory (TRM) T cells provide effective, localized protection against pathogen re-encounter at barrier surfaces. They persist in tissues without recirculation and have little representation among blood lymphocytes. Our work has shown that HSV-specific CD8+ TRM persist in the periphery contiguous to the sensory nerve endings where HSV virion particles are released. These resident, persistent CD8+ TRM exert antiviral effector functions upon re-encountering viral antigen and rapidly eliminate infected cells before the virus can cause clinically symptomatic disease. Current projects are investigating clonal T cell dynamics and the interplay between adaptive and innate immune cells in human genital tissue.

Publications

Zhu J, Peng T, Johnston C, Phasouk K, Kask AS, Klock A, Jin L, Diem K, Koelle DM, Wald A, Robins H, Corey L. Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection. Nature. 2013 May 23;497(7450):494-7.

Peng T, Phasouk K, Sodroski CN, Sun S, Hwangbo Y, Layton ED, Jin L, Klock A, Diem K, Magaret AS, Jing L, Laing K, Li A, Huang ML, Mertens M, Johnston C, Jerome KR, Koelle DM, Wald A, Knipe DM, Corey L, Zhu J. Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes. Front Immunol. 2021 Sep 6;12:735643.

Peng T, Phasouk K, Bossard E, Klock A, Jin L, Laing KJ, Johnston C, Williams NA, Czartoski JL, Varon D, Long AN, Bielas JH, Snyder TM, Robins H, Koelle DM, McElrath MJ, Wald A, Corey L, Zhu J. Distinct populations of antigen-specific tissue-resident CD8+ T cells in human cervix mucosa. JCI Insight. 2021 Aug 9;6(15):e149950. doi: 10.1172/jci.insight.149950. 

Mechanisms driving peripheral nerve regeneration in human skin

After primary infection at the site of acquisition (mouth and genitals), HSV virions travel retrogradely via axons to cell bodies of peripheral sensory neurons, where they establish latency. Reactivation from latency involves anterograde movement to the original site of entry for replication and transmission, causing damage to the nerve and surrounding tissue. We have found that both keratinocytes and neurons produce IL-17c in response to HSV-2 infection and that IL-17c functions to stimulate peripheral nerve growth. Current research in the lab focuses on using spatial transcriptomics to further understand the dynamic process of nerve damage and regeneration.

Publications

Peng T, Chanthaphavong RS, Sun S, Trigilio JA, Phasouk K, Jin L, Layton ED, Li AZ, Correnti CE, De van der Schueren W, Vazquez J, O'Day DR, Glass IA, Knipe DM, Wald A, Corey L, Zhu J. Keratinocytes produce IL-17c to protect peripheral nervous systems during human HSV-2 reactivation. J Exp Med. 2017 Aug 7;214(8):2315-2329. 

Skin-on-chip platform for modeling pathophysiology of skin diseases In vitro

One of the newer avenues of research the lab is pursuing is the development of a skin-on-chip model system. Bio-inspired and micro-engineered 3-D human tissue and organ models provide attractive alternatives for bridging the gap between human and animal models. We have bioengineered a microfluidic-based, full-thickness skin-on-chip infection model that features circulating immune cells and antiviral agents with an endothelialized microvascular network. HSV infection in the skin-on-chip resulted in pathophysiological effects mimicking HSV ulceration in humans. Further, the proof-of-concept application of an antiviral drug demonstrated its outstanding potential for use in an effective and cost-efficient preclinical drug-testing pathway.

Publications

Sun S, Jin L, Zheng Y, Zhu J. Modeling human HSV infection via a vascularized immune-competent skin-on-chip platform. Nat Comm. 2022 Sep 19; 13:5481.