U01AI169587

Dissecting the Mechanisms of HIV Resistance in Vivo to Broadly Neutralizing Antibodies - Abstract

HIV-1 envelope glycoproteins (ENVs) play a crucial role in viral entry into host cells and are the primary target of neutralizing antibodies. Broadly neutralizing antibodies (BNABs) target highly conserved sites on HIV-1 ENVs and have the ability to neutralize a wide range of diverse strains from different clades. However, BNAB immunotherapy, aimed at suppressing HIV-1 replication, can sometimes lead to the development of BNAB-resistant HIV-1 strains. It is important to identify HIV-1 strains with pre-existing BNAB resistance through pre-screening before treatment. Therefore, understanding the underlying mechanisms of BNAB resistance is critical for the future application of BNABs in immunotherapy and prevention.

Mechanisms that lead to multi-BNAB resistance and indirect mechanisms that facilitate the escape of BNABs from different groups are of particular concern for public health. Our study aims to provide important insights into BNAB resistance at different levels. In Specific Aim 1, we will investigate the direct resistance mechanisms of rebounded HIV-1 strains that are resistant to multiple BNABs. We will screen samples from clinical studies of BNAB therapy, identify ENVs of HIV-1 strains that exhibit the highest degree of resistance to several BNABs, study the sequence, function, glycosylation patterns of these ENVs, and determine the structures of resistant ENVs at an atomic level resolution. Our comprehensive approach will provide unique profiles of selected multi-BNAB resistant ENVs that integrate all potential mechanisms contributing to BNAB resistance.

In a parallel direction, we will study the ability of rebounded HIV-1 strains to spread through cell-cell transmission, which allows efficient viral replication in the presence of different groups of BNABs. We will test the hypothesis that BNAB-sensitive HIV-1 strains that replicate despite high levels of BNABs in the serum of participants from the RV397 trial can efficiently spread through cell-cell transmission. Additionally, we will investigate the molecular mechanisms of strains that exhibit increased cell-cell transmission efficiency and BNAB resistance.

In Specific Aim 2, we will define optimal BNAB combinations to overcome BNAB resistance. We will use antibody yeast display technology to bioengineer recombinant BNABs with improved affinity against BNAB-sensitive and resistant HIV-1 strains. This approach will allow us to confirm mechanisms of HIV-1 resistance to BNABs and test the hypothesis that specific changes in BNABs can improve BNAB breadth and enable targeting of a subset of resistant HIV-1 strains.

Overall, our study will provide a high-resolution and comprehensive view of multi-BNAB resistant HIV-1 ENVs, alternative pathways of HIV-1 resistance in vivo, and potential approaches to overcome BNAB resistance. Our results will form a strong basis for the development of new strategies for HIV-1 immunotherapy and prevention efforts.

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93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Minneapolis, Minnesota 554551507 United States

Single Zip Code

Mechanisms of HIV Resistance to Broadly Neutralizing Antibodies (bNAbs) (U01 Clinical Trial Not Allowed) (RFA-AI-21-009)

Amendment Since initial award the total obligations have increased 329% from $1,504,603 to $6,461,018.