Annual Progress Report Summary
Principal Investigator: Bruce Walker
Project: HIV Controllers: Implications for Immunogen Design
Submitted August 1, 2011
Project Goal: To study HIV infected people who have been able to maintain low viral loads without the use of antiretroviral medications and use this knowledge for the design of a global HIV vaccine.
This project, now entering into its final year, has four interdependent elements: patient recruitment for the cohort, immune response characterization in situations of spontaneous control of HIV, identification of the predictable patterns of viral evolution, in response to host immune pressures in situations of spontaneous control of HIV, and the contribution of viral replicative fitness and antigen processing to viral control and immunodominance, and genome-wide association studies. This and other HIV research is critically dependent upon the availability of well-pedigreed human blood samples, and to this end we have used this funding to create an international resource to benefit science well into the future, in that we completed recruitment of >1500 HIV (aviremic and viremic) controllers, and from this large cohort we have identified a select subgroup of individuals for large volume blood donations, longitudinal clinical follow-up, and biological samples. We have also recruited 150 individuals with acute HIV infection.
The path forward to an HIV vaccine depends on eliciting immune responses that have a direct antiviral effect. A major accomplishment to date has been the identification of immune responses that are associated with viral control, and equally importantly, the identification of a large proportion of responses that appear to provide no benefit to controlling HIV, but rather serve as decoys. Those that are antiviral appear to function at least in part by forcing the virus to mutate in ways that render it less able to replicate rapidly, and to cause disease. In the past year, we have further defined the basis for control through targeting of particularly vulnerable regions fo the virus, employing both functional studies and computational methods derived from stock market analysis. These studies have immediate and broad implications for immunogen design.
The design of an effective vaccine will require that we be able to protect against all HIV strains, a scientific challenge of unprecedented proportions, given the immense sequence variability fostered by the poor proofreading of the RT as new viruses are made. We have developed a novel technology in collaboration with the Broad Institute, which allows us to obtain detailed sequence information on the infecting strains, and the evolution of these strains under immune selection pressure. This approach has helped to identify the earliest immune responses to which HIV is actively adapting, enabling us to correlate the ease with which HIV escapes from these responses with the ultimate control of HIV. We have also developed methods to understand how virus infected cells are sensitized for recognition by the immune system, and the factors governing this process. These data are critical to define the sequence space within which HIV must exist, as they directly dictate the design of effective immunogens to counter HIV diversity.
The project on HIV antigen processing has generated new data showing striking differences in the pattern of degradation products generated from various HIV proteins or within each protein tested so far. We have identified sequence signatures linked to efficiency of epitope processing, and are now assessing the links between degradation patterns and immunogenic potential of HIV proteins. We have identified N-flanking and intraepitoic motifs that are involved in regulating the kinetics and the amount of antigenic peptides available for loading onto MHC-I. We have also shown that many naturally occurring mutations flanking or within HIV epitopes evolve toward motifs, preventing the production of HIV epitopes and modifing immune recognition.
The fourth element is a genome-wide association study to determine the host genetic factors associated with persistent viral control. We have identified strong signals in the MHC region regardless of ethnic background of the subjects. In Caucasians these map to three major amino acids at positions 67, 70 and 97 that have the greatest impact on viral control, based on the allelic variants at these positions. As an additional effect related to HLA C expression, we have linked to polymorphisms related to micro RNAs that regulate expression. In the African American cohort, we have further identified a potential role of CD8 binding in control. These data indicate that it is the nature of the presentation of peptide that influences outcome, and paves the way for a mechanistic understanding of what constitutes a good immune responses that can then be applied to vaccine design.
Submitted February 3, 2011 (Interim Report)