Harnessing layers of CD4 T cell immunity for HIV vaccine design

• Applicant: Professor Dr. Hendrik Streeck
• Subject Area: Immunology ; Virology
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317644895

The HIV-1/AIDS pandemic is the most devastating infectious disease in recent history. While potent antiretroviral therapy has been successfully developed, limited access and high costs likely preclude it from slowing the epidemic. A safe, effective, affordable and globally accessible HIV vaccine therefore offers the greatest promise for reducing global rates of HIV infection. Historically, dozens of vaccines have been successfully developed following Pasteurs principle to inject dead or attenuated pathogens (or parts thereof) and have proven to be one of the best interventions for controlling the spread of infectious diseases. However, while we have successfully built vaccines, we do not know the key components of, or the key factors responsible for a protective vaccine-induced immune response. The lack of understanding of the rules that govern the protective effect of a vaccine becomes most apparent in the face of the struggles and surprises we face when developing an HIV vaccine. Indeed, while the RV144 Thai vaccine trial suggested marginal levels of protection fueling optimism that a successful vaccine may be possible, the recent failures of the STEP and Phambili trial put an uncomfortable spotlight on what constitutes a protective vaccine. The moderately successful RV144 trial demonstrated that non-neutralizing antibodies and a small subset of HIV-specific CD4 T cell responses are associated with vaccine-induced protection. Antibody functions are dictated by Tfh cell during the germinal center reaction. However, there is large variability in the functional profile of Tfh cells, which in turn appears to be dictated by their epitope-specificity. Beyond neutralizing activity, antibodies can perform a wide array of different functions such as antibody-dependent cellular cytotoxicity (ADCC), or antibody-dependent cellular phagocytosis (ADCP). Understanding the underlying rules of Tfh dependent antibody function would allow us to specifically modulate and tailor immune responses for specific during vaccine design. The overarching hypothesis of this grant application is that several partially overlapping layers of CD4 T cell anti-HIV immunity exist that have distinct function in the antiviral antibody immunity and that dictate the induction of particular antibody functions. We will first globally determine the rules governing the HIV-specific CD4 T cell responses in chronically HIV infected individuals and will determine on a clonal level the individual influences on B cell programs. Lastly, we will determine the generalizability of those rules and will apply the gained knowledge to an in vivo mouse model.

• DFG Programme: Research Grants