Assessing the Role of HIV-specific IgA glycosylation on transport and function

About This Grant

Summary/Abstract: The advent of antiretroviral therapy (ART) has transformed HIV infection from a fatal disease into a manageable chronic condition. However, people living with HIV continue to experience comorbidities linked to persistent immune activation and inflammation. Unfortunately, there is not a functional vaccine for HIV, and recent efforts to achieve protection through passive immunization with broadly neutralizing anti-HIV IgG antibodies have not been successful. One promising avenue is anti-HIV IgA immunotherapy. Our recent published findings demonstrate that intrarectally applied anti-HIV IgA has an effect on the dissemination of HIV to lymph nodes following intra-rectal challenge. Elucidating the role of biochemical properties, such as glycosylation, on regulating the transport and effector functions of anti-HIV IgA remains poorly understood and requires further investigation. Our previous studies demonstrate that the glycosylation pattern of an anti-HIV IgG monoclonal antibody can influence its ability to disseminate across the blood brain barrier. In addition, we found that glycoengineered IgA isolated from colostrum exhibit altered transport properties. Taken together, these findings support our hypothesis that the glycosylation of IgA influences its cellular transport and can be strategically modified to enhance its transcytosis and function. In aim 1 we will characterize the glycosylation patterns of bulk IgA isolated from people living with HIV and compare them to non-HIV controls. We will then assess how these glycosylation profiles influence endothelial transport and how these changes correlate with viral load. In aim 2 we will clone anti-HIV monomeric IgA and express in 293 freestyle cells that have glycosl- transferases knocked down in order to create glycoengineered IgA. We will define the optimal glycosylation patterns that maximize endothelial transcytosis and antiviral effector functions. We have assembled a team of investigators uniquely equipped to carry out the aims of this grant.