Work

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

Year: 2020

Type: article

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.

Source: JAIDS Journal of Acquired Immune Deficiency Syndromes

DOI: 10.1097/qai.0000000000002301

Authors: Vincenzo Mercurio, Wendy Fitzgerald, Ivan Molodtsov, Leonid Margolis

Institutions: National Institutes of Health, University of Milan, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Gamalei Institute of Epidemiology and Microbiology

Language: English

Topic: HIV Research and Treatment

Subfield: Virology

Field: Immunology and Microbiology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: green

Funders: National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development