Immune escape driven evolution of HIV-1 probed by circulating recombinant forms

• Applicant: Professor Dr. Daniel Hoffmann
• Subject Area: Virology ; Bioinformatics and Theoretical Biology ; Immunology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 391559761

One of the most important defense mechanisms against the Human Immunodeficiency Virus 1 (HIV-1) is recognition of viral fragments by the Human Leucocyte Antigen (HLA) and cytotoxic T lymphocytes (CTLs), leading to the elimination of infected cells. Unfortunately, this mechanism selects mutants of HIV-1 that can evade CTL response. One known way to generate such mutants is by viral recombination. In some cases these recombinant forms can spread in the host population and become so-called circulating recombinant forms (CRFs). Remarkably, most of the HIV-1 infections in China today are caused by CRFs, which motivates our first hypothesis: The high prevalence of specific CRFs in China can be explained by their ability to efficiently evade CTL response in a host population with a specific background of HLA alleles. Our second, related hypothesis (“non-locality” hypothesis) is that HIV-1 in general cannot evade CTL response by local changes of viral genes, despite the recognition of viral fragments by CTL/HLA being local. If the non-locality hypothesis is valid, we have to expect a fundamental impact of viral recombination on the ability of HIV-1 immune escape, which again we will test with CRFs. To test these two hypotheses we will first collect pairs of HLA alleles and HIV-1 genome sequences from publicly available sources and from additional HLA/HIV-1 analyses in China and Germany. Based on these data we will devise a quantitative computational model that allows for the prediction of the effects of specific mutations in CRFs on viral replication and CTL response. These predictions will then be tested experimentally by cellular assays. The project links molecular causes of viral immune escape to the prevalence of viral strains in host populations with specific genomic backgrounds. This knowledge is also relevant for vaccination strategies involving T cell immunity.

• DFG Programme: Research Grants
• International Connection: China
• Partner Organisation: National Natural Science Foundation of China
• Cooperation Partner: Professor Dr. Rongge Yang