GSBS Dissertations and Theses

Approval Date

May 2003

Document Type

Doctoral Dissertation

Department

Graduate School of Biomedical Sciences, Program in Immunology/Virology

Subjects

CD4-Positive T-Lymphocytes; Infant; Child; CD8-Positive T-Lymphocytes; HIV-1; T-Lymphocytes; Academic Dissertations; Dissertations, UMMS

Abstract

Virus-specific cellular immune responses have been shown to be important in the control of viral replication in several animal and human virus models. Cells of both the CD8+ and CD4+ T cell lineages have been shown to play protective roles during viral infections by exerting effector functions that can kill infected host cells or inhibit the production and spread of infectious virions. The continued spread of HIV-1 infection throughout the world, as well as the lack of a prophylactic HIV-1 vaccine have generated much interest in HIV-specific cellular immune responses. Recent technical advances have yielded a tremendous increase in our understanding of HIV-1-specific immunity, as well as HIV-1 replication dynamics and host cell factors that shape the course of acute and chronic infection.

Unfortunately, due to small sample volumes and technological limitations, the study of HIV-1-specific T cell immunity in infants and children has been difficult. An improved understanding of the timing, specificity, and intensity of pediatric HIV-specific T cell responses would contribute to the development of a HIV-1 vaccine for use in regions of the developing world without access to antiretroviral therapeutics.

In the small number of published studies investigating pediatric HIV-specific immunity, T cell responses were uncommonly detected in infants. It remains unclear, however, whether the lack of HIV-specific T cells is an accurate reflection of the in vivo immune state in vertically-infected infants, or rather is a consequence of reagents and assays ill-suited to the detection of low-level and/or diverse T cell responses in pediatric subjects.

In the present dissertation, several methodologies were used to investigate HIV-specific T cell responses in vertically-infected infants and children. HIV-specific CD8+ T cell responses were infrequently detected in a cohort of young infants, but are commonly detected in older infants and children. Interestingly, CMV-specific CD8+ T cell responses were detected in several young infants that lacked HIV-specific responses, suggesting a specific defect in the ability of some infants to generate HIV-specific CD8+ T cell responses. Further experiments characterizing detectable HIV-1-specific CD8+ T cell responses found that the HIV-1 accessory proteins may be important targets of the immune response during early vertical infection. The role of HLA class I genotype and viral sequence are also explored in a pair of vertically-infected twins with discordant CD8+ T cell responses. Finally, viral isolates from an infant with a marked shift in gag-specific epitope usage during infancy are analyzed for the presence of escape mutations.

Gag-specific CD4+ T cell responses were commonly detected in a large cohort of vertically-infected children. A linear relationship between HIV-1 replication and the presence and intensity of HIV-specific CD4+ T cell responses was found, but ongoing HIV-1 replication appeared to blunt CD4+ T cell proliferation.

The data presented in this dissertation describe pediatric T cell immune responses and how they relate to HIV-1 replication. This information may be useful to the design of a prophylactic or therapeutic HIV-1 vaccine for vertically-infected infants and children.

Comments

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