Unraveling the Impact of IL-15 Superagonist N-803 and Broadly Neutralizing Antibodies on HIV Reservoirs for Enhanced Therapeutic Strategies

• Applicant: Dr. Rachel Scheck
• Subject Area: Clinical Infectiology and Tropical Medicine ; Clinical Immunology and Allergology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549131684

The human immunodeficiency virus (HIV) attacks the human immune system, leading to AIDS-defining illnesses and premature death of most infected individuals. Even though antiretroviral therapy (ART) has turned HIV into a manageable chronic disease, there is still no broadly available therapy that can eradicate the virus. One of the major challenges is that HIV integrates its genome into latent immune cells that remain hidden from the immune system and are part of the HIV reservoir. In the quest for a cure, agents that target the reservoir appear to be a promising therapeutic strategy. The long-acting IL-15 superagonist N-803 is a latency-reversing agent that induces virus from the reservoir, activates effector functions, and diminishes the intact HIV reservoir. In combination with broadly neutralizing antibodies (bNAbs), N-803 shows promising results in non-human primates and first clinical studies. This combination leads to long-term post-treatment control in some individuals. This project aims to unravel the underlying mechanisms of post-treatment control by testing samples from clinical trial A5386, where participants receive either N-803 alone or in combination with two bNAbs (VRC07-523LS and 10-1074) targeting two different epitopes. In this trial, an analytical treatment interruption is performed after the completion of the treatment. For this project, we aim to quantify changes in the HIV reservoir of A5386 study participants using a newly developed multicolor digital droplet PCR, which we hypothesize has higher sensitivity and specificity than established methods. It is also planned to characterize immunophenotypes by using the recently established HIV participant-derived xenograft (PDX) mouse model. The PDX mice are transplanted with only differentiated human memory CD4+ T cells and tested for autologous immune effector therapies. They support robust HIV infection without undergoing graft-versus-host disease due to the absence of engrafted naive T cells. It is therefore possible to test samples from controllers of the A5386 trial to identify immune correlates related to reservoir changes. Because of the long-term survival of the mice, this model enables the detection of viral loads and viral escape mutations. Ongoing research indicates that demographic markers are correlated with the size of the intact HIV reservoir and T cell response. Therefore, another aim of this project is to define predictors of long-term viral control after initiating treatment with N-803 and bNAbs. It is planned to identify subcohorts within the A5386 study with different characteristics that might influence the therapeutic response to N-803 and bNAbs, such as age, gender, time of infection, years of ART, or estimated years of infection prior to ART initiation. The aim is to detect inherent biological and demographic differences that may influence the response to reservoir-targeted therapies in order to enhance the understanding of post-treatment control.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Brad Jones