Date of Award

May 2015

Degree Type

Thesis

Degree Name

Master of Science

Department

Biomedical Sciences

First Advisor

Wail M. Hassan

Committee Members

Dean T. Nardelli, Anthony A. Azenabor

Keywords

Lentiviral, Macaques, Rhesus

Abstract

Lentiviral infections of humans and rhesus macaques result in acquired immunodeficiency almost invariably. Yet the duration between the initial infection and the onset of generalized failure of the immune system varies between subjects, in both organisms. Furthermore, acquiring the infection at an older age tends to accelerate disease progression, but mechanisms underlying the latter phenomenon have not been elucidated. It is widely accepted that the events that take place during the very early stages of infection play a critical role in determining disease progression. During this brief period, a fierce competition between viral virulence mechanisms and host immune defenses takes place. I hypothesize that critical immune responses, such as those associated with better outcome in primate lentiviral infections, are lost in rhesus macaques at older age. If true, the loss of these critical immune responses at the early, fate-determining stages of infection would explain rapid progression among those who acquire the infection at older age. Immunological parameters that have been associated with better outcome in primate lentiviral infections include multifunctional T lymphocyte responses, robust proliferative capacity, and production of interleukin 2 (IL-2) (16). Investigating how these immunological parameters change as the animals advance in age may help us predict the possible mechanisms underlying rapid progression in older macaques, and by extension people.

In this study, macaques of advanced age (21 - 29 years) were compared to young adult animals (3 - 7 years). I tested T cell qualities that have been linked to better outcome in primate lentiviral infections in the two age groups. Although most previous studies were based on studied carried out using infected animals, I tested uninfected animals. The rationale is that the observed divergence in infection outcome must have resulted from pre-infection, inherent differences between the two age groups. Post-infection studies can help identify protective responses in an immunologically protected group, while pre-infection studies provide an opportunity to define intrinsic differences in an unaltered immune system that might have resulted in the divergent outcome after infection. Since in primate lentiviral infections the younger population is not protected (since the role is susceptibility in humans and macaques), I do not expect to identify a truly protective immune profile by examining post-infection responses. In fact, some of the potentially important responses can be masked by infection-induced impairments of the immune system. For this reason, I decided to focus this study on pre-infection qualities of T cells.

Due to the large number of variables involved in the current study, I used principal components analysis (PCA) to identify the most discriminatory immunological parameters between the two age groups. PCA was used to enable the simultaneous evaluation of multiple parameters, which provides an advantage over univariate statistical analysis. Since PCA, as well as other multivariate methods, are scarcely used in immunology, which contributes to the novelty of this study. Here, I show that the lentiviral-relevant immune responses, particularly on simian immunodeficiency virus (SIV) I have tested are generally more robust in younger animals compared to animals of advanced age. Younger animals produced more IL-2 in most of the T cell subsets upon both mass and antigen-specific stimulations. Moreover, higher frequencies of multiple cytokine producing cells were also observed in the young group, mainly in CD4+ T cell subsets upon mass stimulation and after exposure to certain antigen-specific stimulants. The data shows an indication of impaired T cell responses in older rhesus macaques that are likely to impact disease progression in primate lentiviral infections. I also show that immunological parameters such as the production of multiple cytokine producing CD4+ and CD8+ T cell subsets were the most important phenotypes in segregating the two age groups, highlighting the potential importance of these immunological qualities for protective immunity.

This study should lay the grounds for the use of multivariate data analysis, particularly PCA, in immune profiling. This approach can potentially be applied to a wide variety of potentially critical areas in HIV or human immunodeficiency virus research, ranging from studying elite controllers to clinical trials, and from studying one arm or tissue of the immune system to studying multiple at once. Therefore, I hope this study will provide new insights to guide future research and ultimately contribute to our understanding of the correlates of immune protection in primate lentiviral infections, particular HIV infection.

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