It is well established that CD8+ cytotoxic T lymphocytes (CTL) are key players in the protective immune response against Human Immunodeficiency Virus Type 1 (HIV-1).
However, there are clear differences in the effectiveness with which particular CTL
control viral infection. Understanding the factors that contribute to the individual
differences in CTL antiviral efficiency will have great implications for vaccine design, as
such information will provide important insights on the mechanism of efficacious antiviral
activity against HIV-1.
One key factor that affects the CTL-mediated antiviral efficiency is the cell-surface
downregulation of human leukocyte antigen class I (HLA-I) mediated by the HIV-1 Nef
protein. While the degree of Nef interference on CTL antiviral efficiency has been shown
to be epitope specific, the factors that determine the susceptibility of CTL to Nef are not
clear. Previous work has indicated that, the timing of epitope expression, functional
avidity, and protein targeting as well as HLA-I restriction can have varying degrees of
influence on how well a CTL can recognize infected cells and suppress HIV-1
replication. The primary goal of this dissertation is to better define the role these factors
play in influencing CTL antiviral activity.
This was addressed using a variety of viral constructs, and HIV-1 specific CTL clones.
In Chapter Three, I first examine CTL susceptibility to Nef-mediated HLA-I
downregulation using a previously described viral suppression assay, and identify
epitope properties that determine susceptibility to Nef. Then in Chapter Four, I focus on
the role of protein targeting in CTL antiviral activity. I specifically compare the role of
Gag versus Env targeting in viral suppression efficiency, using viral constructs where a
Gag epitope is translocated to the Env protein.
The data presented in this dissertation show that the kinetics of epitope presentation are
an important determinant of CTL antiviral activity. Individual epitope presentation
kinetics vary independently of protein, and the earlier the epitope is presented on the
cell surface before Nef-mediated HLA-I downregulation, the more effectively CTL can
eliminate virus-infected cells and suppress viral replication. Factors including protein
properties, HLA-I restriction of the epitope, and functional avidity, are poor predictive
properties of Nef susceptibility and CTL antiviral efficiency. Together these results
suggest that the properties of individual epitopes, such as epitope expression kinetics,
most strongly influence CTL antiviral activity. Lastly, future research could potentially
focus on the role of host factors, such as T cell receptor functions, in determining CTL
antiviral activity against HIV-1. A few proposed ideas are summarized in Chapter Five.