Speaker: Dr. Ruhong Zhou, IBM Watson Research Center, Columbia University
Title: HIV Vaccine Development: Binding Free Energy of TCR/peptide/HLA Complexes
Abstract: The design and development of HIV vaccines has been of great interest in recent years due to the wide spread infection of AIDS, with more than 34 million individuals in the world living with HIV. Immune control of viral infections is modulated by diverse T cell receptor (TCR) clonotypes engaging peptide-HLA class I complexes on infected cells, but the relationship between their structure and antiviral function is largely unclear. In this talk, I will describe some of our recent works on this critical HIV/AIDS vaccine development through collaborative efforts. With a combined in silico and in vivo approach, we studied the TCR/peptide/HLA interactions from multiple clonotypes specific for a well-defined HIV-1 epitope, and found that effective and ineffective clonotypes bind to the terminal portions of the peptide-HLA through similar salt bridges, but their hydrophobic side-chain packings can be very different, which accounts for the major part of the differences among these clonotypes. Non-specific hydrogen bonding to viral peptide also accommodates greater epitope variants. Together with state-of-the-art free energy perturbation calculations for point mutations on viral peptide, our results clearly indicate a direct structural basis for heterogeneous T cell antiviral function. Meanwhile, we also sought to understand the mechanisms by which natural killer (NK) cells recognize HIV-1-infected cells and how this virus can evade NK cell-mediated immune pressure. Two sequence mutations (in p24 Gag) were identified in a large cohort of untreated HIV-1 clade C-infected individuals from South Africa (N=392), suggesting viral escape from NK cells through sequence variations within HLA class I-presented epitopes. Again, our structural modeling and surface plasmon resonance experiments of KIR/peptide/HLA complexes revealed the underlying molecular mechanisms governing the three way complex interaction and recognition. Future studies will be needed to assess processing and antigen presentation of the investigated HIV-1 epitope in natural infection, and the consequences for viral control.