Characterization of HIV-1 Antibody Resistance in Humans and its Impact on Viral Fitness

• Applicant: Privatdozent Dr. Philipp Frederik Schommers
• Subject Area: Clinical Infectiology and Tropical Medicine ; Virology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 495793173

BackgroundAntiretroviral therapy (ART) is the gold standard for the treatment of HIV infection. These drugs are highly effective in suppressing replication of the virus but require lifelong daily application and can be associated with side effects. Moreover, although effective ART has been available for about 20 years now, there are still 1.5 million new HIV infections and 700.000 AIDS-related deaths per year. Thus, next-generation therapies and approaches to treat, prevent, or even cure HIV-1 infections are urgently needed. Broadly neutralizing antibodies (bNAbs) that are highly active against HIV-1 represent such a promising novel approach. With their very long half-life, the activation of innate effector responses and an enhancement of host immunity to HIV-1, these bNAbs have several advantages compared to currently available antiretroviral therapy. Clinical trials have demonstrated the potential of bNAbs in treating and preventing HIV-1 infections. However, de novo and pre-existing HIV-1 antibody resistances (HIVAR) due to mutations in the HIV-1 envelope protein (HIV-1env) are not well understood yet and pose a critical problem for the clinical use of bNAbs. Furthermore, besides hampering the clinical use of bNAbs, HIVAR also will play a major role in future design of an HIV-1 vaccine that requires the elicitation of bNAbs to which the circulating strains are sensitive. However, currently available assays to detect HIVAR are not accurate enough, very labour and cost-intensive and take too long in order to be used in a widespread clinical use.AimsThus, I here aim to develop a novel pipeline to rapidly detect HIVAR in HIV-1 infected humans. Screening of large cohorts for HIVAR will help to characterize and understand viral resistance mechanisms and to better predict a patient’s antibody sensitivity for future clinical studies. To this end we will i) develop a novel and innovative pipeline to rapidly detect HIV-1env sequences and test their antibody sensitivity and ii) use this pipeline to characterize the HIV-1env variability and viral resistance mechanisms in a large cohort of HIV-1 infected individuals. This dataset will then be used to develop a novel computational prediction tool that can predict HIVAR in HIV-1 infected patients. Finally, we will assess the impact of HIVAR on viral fitness in vitro and in vivo in humanized mice. This will enable us to target vulnerable sites of HIV-1 with future bNAbs and/or bNAb-inducing vaccines. As a result, the proposed research project is of highest relevance since I will here develop methods to better identify, characterize and understand HIVAR.ConclusionIn summary, this proposed translational research project will enhance our understanding of HIVAR and thus, will have a significant impact on the design of bNAb treatments and the efficacy of HIV-1 vaccines.

• DFG Programme: Independent Junior Research Groups