Induction, maintenance, and function of genital tract-resident CD8+ T cells

生殖道驻留 CD8 T 细胞的诱导、维持和功能

• 批准号: 8975361
• 负责人: Gregg N. Milligan
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8975361
• 关键词: American; Animal Model; Antigens; CD8B1 gene; Cavia; Cell Communication; Cell physiology; Cells; Cellular Immunity; Cessation of life; Chronic; Clinical; Clinical Trials; Development; Disease; Economic Burden; Epithelium; Event; Female; Frequencies; Future; Genital system; Goals; HIV; Health; Hepatitis B Virus; Herpes Simplex Virus Vaccines; Human; Human Herpesvirus 2; Human Papillomavirus; Immune; Immune response; Immunization; Individual; Infection; Laboratory Animals; Licensing; Maintenance; Mediating; Memory; Methods; Modeling; Morbidity - disease rate; Mucous Membrane; Mus; Nature; Newborn Infant; Play; Population; Population Sizes; Prevention; Property; Proteins; Reagent; Recurrence; Recurrent disease; Regimen; Risk; Role; Route; Sexually Transmitted Diseases; Simplexvirus; Site; Symptoms; T cell response; T memory cell; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Treatment Efficacy; Ursidae Family; Vaccines; Vagina; Viral; Virus; Virus Diseases; Virus Shedding; Woman; Women' s Health; Work; aged; base; disorder control; efficacy testing; experience; genital herpes; genital infection; health economics; immunoregulation; mathematical model; neonate; pathogen; preclinical study; prevent; prophylactic; public health relevance; reactivation from latency; reproductive; response; seropositive; therapeutic vaccine; transmission process; virus development

 DESCRIPTION (provided by applicant): Approximately 16% of Americans aged 14-49 are currently seropositive for Herpes simplex virus type 2 (HSV- 2) and worldwide, 23 million new infections occur each year. Infection of neonates and immune compromised individuals results in serious morbidity or death. Further, HSV-2 infections increase the risk of acquisition of HIV. Immunization would be the most effective approach to control HSV-2, but prophylactic vaccines that elicit systemic immune responses against HSV-2 have failed in clinical trials. Preclinical studies with HSV-2 infected mice and humans have suggested that the presence of virus-specific T cells at the site of viral infection in the genital epithelia may be critical for effectve protection of the genital epithelia. These cells are strategically located to protect against re-infection and to interfere with HSV-2 shedding in the genital tract thereby impacting HSV-2 transmission. Mathematical models of the interaction of these cells with the reactivated virus suggest that genital-resident memory T cells may determine the duration of HSV-2 shedding and that stimulating these cells therapeutically may impact virus shedding; however, a clear demonstration of this protective role is lacking. Understanding the function of these cells in modulation of HSV-2 shedding and how to induce these cells with vaccines requires an animal model that accurately reflects the pathogenic events of HSV-2 as they occur in humans. Guinea pigs are the only common laboratory animals that experience spontaneous reactivation and virus shedding events during latent HSV-2 infection that are similar to those experienced by infected humans and represent the best model to test hypotheses of immune modulation of HSV-2 recurrent shedding. Using this model, our central hypothesis is that these cells play a critical role in modulating the frequency and/or magnitude of HSV-2 shedding and in limiting the extent of vaginal epithelium infection during HSV-2 shedding events. Further, the magnitude of this cell population can be effectively enhanced by therapeutic immunization with a replication defective HSV-2 vaccine. Our long term goal is to develop therapeutic vaccines that will enhance the number and function of HSV-specific genital tract resident T cells to protect the female genital mucosa against recurrent disease and control recurrent HSV-2 shedding in individuals that do become infected, therefore impacting HSV-2 transmission. The objective of this application is to understand the impact of virus-specific genital-resident T cells on virus shedding after reactivation of HSV- 2 from latency. Aim 1 will determine the role of genital-resident, HSV-specific memory T cells in modifying the frequency and/or magnitude of HSV-2 shedding following natural HSV-2 reactivation. Aim 2 will determine if the efficacy of therapeutic immunization in modulating recurrent disease and virus shedding can be optimized by specifically enhancing the magnitude of HSV-specific genital-resident T cell populations. This work is significant because understanding the role of virus-specific T cells residing in the genita tract at the site of HSV-2 shedding will be critical for development of therapeutic vaccines to reduce HSV-2 transmission.