EMERGING CHALLENGES IN HIV AND AGING: ROLE OF A GLYCAN-BINDING IMMUNOMODULATORY LECTIN

Abstract

Despite antiretroviral therapy, people living with HIV have an increased risk for and earlier onset of age-related comorbidities including cardiovascular, kidney, liver, bone, and neurologic disease. About half of the population living with HIV in the U.S. is older than fifty years of age and this trend to an older demographic is expected to continue. Although multifactorial, evidence suggests chronic inflammation and immune activation, thought to stem from occult viral replication and the senescence, exhaustion, and premature aging of the immune system, are key drivers of early development of these comorbidities. Identifying reliable biomarkers to predict disease progression, determining key pathways in comorbidity development, and developing novel interventions to mitigate these complications are warranted as people with HIV age. One key regulator of immunological functions is interactions between cell-surface glycans and glycan-binding proteins, particularly galectins, a family of soluble β-galactoside-binding lectins. In particular, galectin-9 (Gal-9), a pleiotropic mediator of innate and adaptive immune responses, is elevated in the plasma during early HIV infection and remains high after ART suppression compared to people without HIV. Gal-9 is associated with HIV disease progression, the severity of age-related comorbidities, and can induce HIV transcription and reactivate latent virus. Investigating the significance of Gal-9 in the older HIV+ population could lead to the development of novel therapies to improve immune functionality, and reduce inflammation-associated co-morbidities, during ART-suppressed HIV infection. Our in vitro and ex vivo data show that Gal-9 mediates both HIV transcription and T cell activation through Lck-dependent mechanisms, indicative of a TCR activation pathway. We determined the potential of Gal-9 to serve as a biomarker of morbidity and mortality risk in HIV. Our data illustrate a link between cerebrospinal levels of Gal-9 with poor cognitive performance central nervous system immune activation, as well as plasma Gal-9 levels and mortality risk and the burden of comorbid disease among older people living with HIV. Finally, given that the functionality of endogenous Gal-9 during the course of HIV infection is not fully known and targeting Gal-9-induced pathways in vivo are limited, we generated anti-Gal-9 monoclonal antibodies with high specificity and limited off-target effects that can be used to target Gal-9 pathways in vivo in various animal models of HIV infection. Our work provides a framework in guiding the understanding of glycan-galectin interactions in the pathogenic mechanisms of age-related disorders in older HIV-infected individuals on suppressive ART and the relationship between aging, HIV, and inflammation.