Current combinations of antiretroviral therapy (ART) achieve durable suppression of HIV replication, accompanied by recovery and preservation of the immune system. However, despite this prolonged suppression of HIV replication, ART does not completely attenuate indices of activation and inflammation in the majority of people living with HIV (PWH). The persistence of inflammation during ART-treated HIV infection has been linked to harmful health consequences including higher rates of co-morbidities, non-AIDS events, and mortality. The mechanisms underlying these observations have not been fully elucidated and the increased survival of PWH, due to the benefits of ART, now warrant a better understanding of the pathogenesis of HIV infection. Therefore, the identification of critical determinants in the inflammatory process and understanding their role in disease outcome are major priorities of HIV research.

There has been growing evidence in recent years supporting the role of extracellular vesicles (EVs) in several pathological processes (e.g., cancer, rheumatological, cardiovascular and neurological diseases, viral infections), including HIV infection. EVs are a heterogeneous group of membrane vesicles secreted by different types of cells into different bodily fluids including blood, urine, saliva, serum or breast milk. Interest in this field is now focused on their roles in normal physiological and pathological cellular processes (Van Niel et al., Nat Rev 2018; Fitzgerald et al., Sci Rep 2018). Several studies have identified EVs as new players in the pathogenesis of HIV infection as vehicles for intercellular communication (Poveda et al., AIDS Rev 2017). Indeed, EVs have been implicated in the transport of inflammatory cytokines, which are small proteins secreted by a broad range of cells that are key modulators of immune and inflammatory responses. The levels of pro-inflammatory cytokines during HIV infection have been traditionally measured directly in plasma samples, but since several studies have found cytokines encapsulated in and embedded on the surface of circulating EVs, it seems fascinating to evaluate the profile and levels of these EV-associated pro-inflammatory cytokines during HIV infection (Fitzgerald et al., Sci Rep 2018; Konadu et al., J Infect Dis 2015).

The profile and levels of several pro-inflammatory cytokines associated with plasma EVs have been assessed in well-characterized cohorts of PWH with different viro-immunological status in a study presented at CROI 2022 (Poveda et al., CROI 2022; Abstract 225). Higher levels of EV-associated cytokines were observed for plasma EVs recovered from PWH compared to EVs from HIV uninfected donors, and levels were especially higher for a cohort of elite controllers – a population of PWH able to spontaneously control HIV replication without ART. Additionally, the levels of specific cytokines associated with EVs have been identified as signatures for HIV status. The results of this study increase our knowledge concerning the pathogenesis of HIV and allow the identification of new biomarkers associated with inflammatory environments that persist during HIV infection even in absence of HIV replication.

Eva Poveda1 and Michael L. Freeman2

1 Galicia Sur Health Research Institute

Complexo Hospitalario Universitario de Vigo

SERGAS-UVigo, Spain

HIV&Co founder and CEO

Contact: evapoveda@hivandco.com

2 Case Western Reserve University
Division of Infectious Diseases

Cleveland, Ohio, USA

The Role of Extracellular Vesicles during HIV infection