Saturday, May 10, 2025
5/10/2025
Impact of NETosis on SIV Pathogenesis and Response to Treatment - Antiretroviral therapy (ART) has dramatically changed the landscape of chronic HIV infection and massively reduced mortality in persons living with HIV (PWH). Yet, many PWH present with intestinal dysfunction, residual immune activation and inflammation, incomplete immune restoration and a hypercoagulable state, all of which drive a poor prognosis and development of non-AIDS comorbidities, such as the cardiovascular disease (CVD). The pathways involved in the development of CVD in PWH and SIV-infected macaques are not completely elucidated. We recently reported that neutrophil dysfunction may be a key driver of this process, through overwhelming activation and excessive production of neutrophil extracellular traps (NETs). By studying the dynamics and functions of NETs in SIV infection, we showed that they may contribute to disease progression and comorbidities: (a) proinflammatory NETosis increases throughout untreated SIV infection, and is only partially reduced by ART, (b) NETs may be a determinant of the indiscriminate depletion of immune cells that are not virus targets, and of the incomplete CD4+ T cell restoration observed in PWH on ART, and (c) NETosis may promote thrombosis in the thrombocytopenic environment of HIV/SIV infections by capturing platelets and expressing tissue factor. We thus propose a project to assess the role of NETosis in HIV disease progression and response to ART through a direct intervention in vivo. We will use an SIVsab/PTM model developed in our laboratory that faithfully reproduce both key aspects of SIV pathogenesis on ART and the CV disease. We will also use a NET inhibitor that has been validated in vivo by numerous studies in murine animal models. In preliminary studies, we demonstrated that this drug has the ability to inhibit ex vivo production of NETs by neutrophils isolated from our SIV-infected PTMs. We will first test the hypothesis that NETosis is involved in driving SIV pathogenesis and disease progression. To this goal, we will administer the NET inhibitor during chronic infection to untreated SIV-infected PTMs and assess its impact on the natural history of SIV infection, including CV comorbidities. These experiments are designed to model those PWH who either do not receive ART or do not achieve complete virus suppression on ART. Second, we will test the hypothesis that NETosis is involved in driving the response to ART and development of CV comorbidities. To this goal, we will administer a NET inhibitor to ART-treated SIV-infected PTMs and assess the consequences of this intervention on the CD4+ T cell restoration, inflammation, coagulation and CV disease development. These experiments are designed to model PWH, who receive ART. This highly innovative project will improve our understanding of HIV pathogenesis and mechanisms of HIV-related comorbidities, particularly the CVD, a major cause of death in PWH, and thus may have a critical impact on the clinical management and survival of the PWH.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).