Persistent Immune Activation in HIV-1–Infected Ex Vivo Model Tissues Subjected to Antiretroviral Therapy: Soluble and Extracellular Vesicle-Associated Cytokines. (1st May 2020)

• Record Type: Journal Article
• Authors: Mercurio, Vincenzo; Fitzgerald, Wendy; Molodtsov, Ivan; Margolis, Leonid
• Is Part Of: Journal of acquired immune deficiency syndromes. Volume 84:Number 1(2020)
• Publication Date: 2020-05-01
• Subjects: cellular factors/cytokines -- HIV -- ART -- extracellular vesicles -- ex vivo tissues; AIDS (Disease) -- Periodicals; Acquired Immunodeficiency Syndrome -- Periodicals; AIDS (Disease); Periodicals; 616.9792005
• DOI: 10.1097/QAI.0000000000002301
• Languages: English
• ISSNs: 1525-4135

Abstract

Abstract : Background: Residual immune activation after successful antiretroviral therapy (ART) in HIV-1–infected patients is associated with the increased risk of complications. Cytokines, both soluble and extracellular vesicle (EV)-associated, may play an important role in this immune activation. Setting: Ex vivo tissues were infected with X4LAI04 or R5SF162 HIV-1. Virus replicated for 16 days, or tissues were treated with the anti-retroviral drug ritonavir. Methods: Viral replication and production of 33 cytokines in soluble and EV-associated forms were measured with multiplexed bead-based assays. Results: Both variants of HIV-1 efficiently replicated in tissues and triggered upregulation of soluble cytokines, including IL-1β, IL-7, IL-18, IFN-γ, MIP-1α, MIP-1β, and RANTES. A similar pattern was observed in EV-associated cytokine release by HIV-infected tissues. In addition, TNF-α and RANTES demonstrated a significant shift to a more soluble form compared with EV-associated cytokines. Ritonavir treatment efficiently suppressed viral replication; however, both soluble and EV-associated cytokines remained largely upregulated after 13 days of treatment. EV-associated cytokines were more likely to remain elevated after ART. Treatment of uninfected tissues with ritonavir itself did not affect cytokine release. Conclusions: We demonstrated that HIV-1 infection of ex vivo lymphoid tissues resulted in their immune activation as evaluated by upregulation of various cytokines, both soluble and EV-associated. This upregulation persisted despite inhibition of viral replication by ART. Thus, similar to in vivo, HIV-1–infected human tissues ex vivo continue to be immune-activated after viral suppression, providing a new laboratory model to study this phenomenon. Abstract : Supplemental Digital Content is Available in the Text.