Annual Progress Report Summary
Principal Investigator: Bruce Walker
Project: HIV Controllers: Implications for Immunogen Design
Submitted February 1, 2010 (Interim Report)
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 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.
The foundation of the grant is cohort development. We have completed recruitment of >1500 HIV (aviremic and viremic) controllers to support activities 2 through 6. From this large cohort we have identified a select subgroup of individuals for large volume blood donations and longitudinal clinical follow-up and biological samples. We have recruited 58 individuals with acute HIV infection.
The second component, which focuses on adaptive responses, is designed to understand how T cell responses mediate viral control. We have used new technologies to demonstrate that epitope-specific immune responses differ markedly in their ability to inhibit virus replication, and that pathways to immune escape differ in elite controllers. Moreover, we have examined eighteen rare cases of acute HIV-1 infected subjects who subsequently became elite controllers, showing that viral fitness in the earliest stages of infection is associated with outcome. We are also currently performing a detailed analysis of the interaction of CD4+ T cell help and CD8+ T cell responses, and we are in the process of further characterizing HIV-1-specific CD4+ T cells.
The third element, viral evolution and antigen processing, has made great strides in technology development and scientific results. We have made considerable progress in terms of development of the new 454 pyrosequencing technology for viral sequencing.. This approach, which included the development of novel assembly and error detection algorithms will enable an unprecedented in-depth analysis of the viral quasi-species in each individual. We have also identified a unique set of mutations in Gag which dramatically impair viral replication and are associated with protective HLA class I alleles, supporting the importance of vaccine targeting of only the most conserved regions of HIV.
The project on HIV antigen processing has generated new data indicating that it may possible to control HIV epitope production. We have identified N-flanking motifs regulating the kinetics and the amount of antigenic peptides produced, and in altering the amount of epitopes available for loading onto MHC-I. Additionally we have identified HLA-restricted polymorphisms that limit either the trimming of peptides into epitopes or the pool of epitopes produced inside cells and reduce recognition by epitope-specific CTL, suggesting that naturally occurring HIV mutations may alter various steps of antigen processing to limit immune recognition.
The fourth element is a genome wide association study to determine the host genetic factors associated with persistent viral control. We have found a strong signal in the MHC region regardless of ethnic background of the subjects, and have found over 60 single nucleotide polymorphisms that reach genome wide significance, indicating that host immune responses are likely critical in persistent containment of HIV.