Exploring the nature of CD8+ T cell efficacy in HIV infection – EFFIVIT8

From isolated case reports, the scale of the human immunodeficiency virus (HIV) epidemic has become a global pandemic, and HIV the most extensively studied and notorious pathogen in history. 35 million people are estimated to live with HIV by the end of the 2008. Based on compelling evidence that CD8+ T cells are key players in the immune response to HIV, the scientific community has focused enormous efforts on the development of therapeutic and prophylactic vaccines that elicit T cell responses with the premise that such interventions will be sufficient to confer protective effects against HIV. To date however, the development of effective T cell vaccines remains elusive, which is highlighted by the recent failure of the Merck STEP study, the most ambitious clinical trial performed to date to tackle the HIV pandemic. Consensual opinion is that our general understanding of T cell efficacy against viruses in humans is actually still limited. Without such knowledge, vaccine design strategies will remain largely empirical and further failures are likely. Although it is clear that CD8+ T cell efficacy depends on qualitative rather quantitative attributes, the exact nature of effective CD8+ T cells remains poorly understood. The study of CD8+ T cell immunity is the central theme of my research. During the last 10 year period, my work has focused on the characterization of CD8+ T cells in different contexts, infectious or cancerous. The research program I am proposing to perform here is in the direct continuity of this work and represents the synergy of my expertise acquired in Oxford, Lausanne and Paris. The aim of the present proposal is to better understand the factors that rule the development and maintenance of effective CD8+ T cell responses against HIV. I have recently reported that CD8+ T cells associated with superior control of HIV replication present a high sensitivity for HIV antigens. The level of antigen sensitivity determines the strength of the stimulus received by T cells on exposure to defined densities of cognate antigen. Since the functional outcome of antigen engagement depends on the derived stimulus, the degree of sensitivity has consequences beyond those for simple T cell activation kinetics. Based on the premise that antigen sensitivity is central for CD8+ T cell efficacy, I propose to return to basic science to explore in details various aspects of CD8+ T cell generation and function in HIV infection. I plan to use a variety of approaches based on well established and novel technologies, together with the privileged access to a variety of biological samples available at the Hôpital Pitié Salpétrière in Paris, where I am established. I propose to investigate several issues that are central for our understanding of the establishment of effective CD8+ T cell responses in humans; the project is divided in 4 parts accordingly: 1. Importance of naïve HIV reactive CD8+ T cell precursor frequency for efficacy of CD8+ T cell responses. The frequency of naïve T cell precursors reactive for specific HIV antigens may be directly related to the qualitative attributes of CD8+ T cell memory populations, for instance by providing a more diverse clonotypic repertoire, from which selection of high quality clonotypes (i.e. with high antigen sensitivity) may be more probable. 2. Significance and interplay of the different attributes of CD8+ T cell efficacy. The interplay between the major factors important for CD8+ T cell efficacy in HIV infection (HLA restriction, target epitope and antigen sensitivity) and their respective weight for anti-viral efficacy remain unclear. 3. Determinants of antigen sensitivity at the effector-target interaction level. Beyond the affinity of the expressed T cell receptor (TCR) for antigen, other factors related to the CD8+ T cell itself or to the target cell and viral factors may be important for antigen sensitivity and ultimately affect efficacy to suppress HIV replication. 4. Exhaustion of immune resources and maintenance of effective CD8+ T cells. Continuous renewal of exhausted antigen specific T cells is crucial for the maintenance of effective immunity against persistent viruses. However, the renewal of effective CD8+ T cells may be compromised in HIV infected patients, due to the exhaustion of global primary immune resources during the infection.