The Role of gp120 on Cardiovascular Disease in People Living with HIV

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Project Summary/Abstract Chronic infection with human immunodeficiency virus (HIV) is characterized, despite the use of potent antiretroviral therapy (ART), by the presence of low-grade inflammation and immune activation leading to multiple age-related non-infectious comorbidities such as cardiovascular disease (CVD). The HIV envelope glycoprotein 120 (gp120) plays a vital role in viral entry; however, this protein can be shed from the virion or cell surface associated envelope trimer as soluble gp120 (sgp120) and is present in the blood and tissues. It has been suggested that sgp120 contributes to HIV pathogenesis and immune dysfunction through immunoregulatory activities that induce production of pro-inflammatory cytokines and chemokines. There have also been reports of significant levels of sgp120 in the plasma of individuals on ART with undetectable viral loads [1]. CVD remains the leading cause of death in people living with HIV (PLWH) in the United States with a disproportionate burden on racial and ethnic minorities such as Native Hawaiian and Other Pacific Islanders (NHOPI) with high CVD risk factors including obesity, hypertension, dyslipidemia, and diabetes. Therefore, sgp120 induced inflammation in predisposed NHOPI is likely to be an added source of chronic inflammation driving the higher burden of CVD in NHOPI living with HIV. A limiting factor in exploring the role of sgp120 in CVD is the lack of a reliable assays to quantitate sgp120 in samples such as plasma. Current sgp120 enzyme-linked immunosorbent assay (ELISA) kits cannot detect genetically diverse sgp120 variants because antibodies may not cross-react, leading to false-negative results. To obtain more accurate sgp120 measurements, detection antibodies need to be expanded and carefully selected to ensure they can recognize and bind to diverse sgp120 variants present in PLWH. The lack of a reliable and sensitive assay is a barrier to understanding the role that sgp120 plays in CVD in PLWH. The overall objective of this proposal is to understand the contributory role of gp120 in chronic inflammation in PLWH by first improving the ability to quantitate sgp120 in clinical samples. We propose to utilize and validate a novel approach to measuring sgp120 in the plasma of PLWH by creating a bead-based inhibition assay and compare improvements in sgp120 variant detection over commercially available ELISA kits. Second, we will utilize the same antibodies used in the inhibition in an immunohistochemistry approach to identify the cell source of sgp120 in lymphoid tissue within lymph nodes and rectal tissue of aviremic PLWH on ART. Finally, we will assess the relationship of sgp120 to inflammatory markers and to subclinical CVD in PLWH. The significance of this project is that improved detection of sgp120 will advance our understanding of how sgp120 contributes to CVD during chronic or virally suppressed HIV infection.