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The Determinants of CD8+ Cytotoxic T Lymphocyte Antiviral Activity Against Human Immunodeficiency Virus Type 1


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.

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