Postdoctoral Research Fellow
Fellow or Postdoc
Sarvesh Chelvanambi, Julius Decano, Yoshihiro Yanagihara, Amelie Jule, Yuto Nakamura, Shin Mukai, Takashi Enomoto, Constance Delwarde, Francesca Bartoli-Leonard, Prabhash Jha, Adrien Lupieri, Joan Matamalas, Takeshi Tanaka, Diego V Santinelli-Pestana, Rile Ge, Mary Whelan, Katelyn Perez, Taku Kasai, Shiori Kuraokae, Shannan Ho Sui, Abhijeet Sonawane, Sasha A. Singh, Elena Aikawa, and Masanori Aikawa
Background: People living with HIV (PLWH) on anti-retroviral therapy remain at risk for cardiovascular diseases, including atherosclerosis. We hypothesized that persistent viral protein (HIV-Nef) in extracellular vesicles (EVs) promotes inflammation by altering macrophage heterogeneity, contributing to cardiovascular disease.
Methods and Results: Human primary macrophage heterogeneity was characterized stimulation with EVs engineered to contain HIV-Nef by simultaneous scRNA-seq & scATAC-seq integrated with Weighted Nearest Neighbor method. Among 16 clusters (50,931 cells; 4 do) pseudotime (Slingshot), gene regulatory network (DoRothEA and pySCENIC) and motif accessibility (ChromVar) analyses demonstrated that HIV-Nef regulates 2 inflammatory clusters with differentially active and accessible transcription factors. Whole cell and sub-cellular compartmentalized proteomics identified differentially abundant proteins associated with nucleus (662 proteins), cytosol (461), DNA (261) EVs (132), and cell surface (72), suggesting changes in immune response pathways. Functional phenotyping showed HIV-Nef impairs macrophage functionality by suppressing atheroprotective efferocytosis, promoting chemotaxis and altering cell metabolism. Injection of HIV-Nef EVs into male and female Ldlr-/- mice impaired macrophage efferocytosis, increased plasma inflammatory cytokines, enhanced atherogenesis and promoted infiltration of macrophages into aortic root.
Conclusions: Persistent Nef in EV in PLWH may modulate macrophage heterogeneity to promote chronic inflammation.These findings may help identify at-risk patients and develop novel atheroprotective therapies.
Anti-retroviral therapy (ART) has been a game-changer for people diagnosed with HIV. It has allowed them to live without developing AIDS for many years. However, as HIV-positive individuals grow older, they face a higher risk of developing cardiovascular disease. This happens at an earlier age, even if their HIV is well controlled with medication.
ART drugs are effective in keeping HIV levels in the blood undetectable, which is great news. But, surprisingly, even in patients with undetectable virus levels, there’s a persistent viral protein called Nef that keeps circulating in their bodies. Nef manages to escape from the hiding spots where HIV lurks and moves freely throughout the body.
Nef has the ability to infiltrate and hijack human cell signaling. It makes cells more prone to causing inflammation and disrupts their normal functioning. In experiments with mice, Nef alone was shown to speed up the development of cardiovascular disease.
Understanding how Nef takes control of human cells is crucial. It can help us figure out why people living with HIV often develop cardiovascular disease and lead to better treatments for those affected by HIV.