The Youngbloods. Get Together. Hypercoagulation, Complement, and NET Formation in HIV/SIV Pathogenesis

Theresa A Reno,Irini Sereti,Lilas Tarnus,Russell Tracy,Ivona Pandrea,Cristian Apetrei,Alan L Landay

doi:10.3389/fviro.2021.795373

Abstract

Chronic, systemic T-cell immune activation and inflammation (IA/INFL) have been reported to be associated with disease progression in persons with HIV (PWH) since the inception of the AIDS pandemic. IA/INFL persist in PWH on antiretroviral therapy (ART), despite complete viral suppression and increases their susceptibility to serious non-AIDS events (SNAEs). Increased IA/INFL also occur during pathogenic SIV infections of macaques, while natural hosts of SIVs that control chronic IA/INFL do not progress to AIDS, despite having persistent high viral replication and severe acute CD4+T-cell loss. Moreover, natural hosts of SIVs do not present with SNAEs. Multiple mechanisms drive HIV-associated IA/INFL, including the virus itself, persistent gut dysfunction, coinfections (CMV, HCV, HBV), proinflammatory lipids, ART toxicity, comorbidities, and behavioral factors (diet, smoking, and alcohol). Other mechanisms could also significantly contribute to IA/INFL during HIV/SIV infection, notably, a hypercoagulable state, characterized by elevated coagulation biomarkers, including D-dimer and tissue factor, which can accurately identify patients at risk for thromboembolic events and death. Coagulation biomarkers strongly correlate with INFL and predict the risk of SNAE-induced end-organ damage. Meanwhile, the complement system is also involved in the pathogenesis of HIV comorbidities. Despite prolonged viral suppression, PWH on ART have high plasma levels of C3a. HIV/SIV infections also trigger neutrophil extracellular traps (NETs) formation that contribute to the elimination of viral particles and infected CD4+T-cells. However, as SIV infection progresses, generation of NETs can become excessive, fueling IA/INFL, destruction of multiple immune cells subsets, and microthrombotic events, contributing to further tissue damages and SNAEs. Tackling residual IA/INFL has the potential to improve the clinical course of HIV infection. Therefore, therapeutics targeting new pathways that can fuel IA/INFL such as hypercoagulation, complement activation and excessive formation of NETs might be beneficial for PWH and should be considered and evaluated.

Highlights

Antiretroviral therapy (ART) has increased the life expectancy and reduced morbidity and mortality for persons with HIV (PWH), becoming one of the most successful interventions of the twentieth century, that turned a virtually 100% deadly condition into a chronic disease [1]
The microbial translocation observed during pathogenic HIV/SIV infection can lead to the activation of all complement pathways: (i) the lectin pathway via the recognition of Pathogen Associated Molecular Patterns (PAMPs), (ii) the alternative pathway via LPS, (iii) the classic pathway, which is triggered by the inflammation through LPS and the production of CRP, that can bind to C1q [178]
While the pathogenic HIV and SIVmac are trapped in germinal centers of humans and macaques, respectively, this phenomenon is less frequent in non-pathogenic SIV infections of the natural African Non-human primate (NHP) hosts [32, 198,199,200,201], indicating that deposition of complement-opsonized viral particles in the lymphoid tissues might be critical for disease progression

Summary

Introduction

Antiretroviral therapy (ART) has increased the life expectancy and reduced morbidity and mortality for persons with HIV (PWH), becoming one of the most successful interventions of the twentieth century, that turned a virtually 100% deadly condition into a chronic disease [1]. This is supported by the fact that, over a 20-year follow-up of SIV infections in natural hosts, only a handful of cases of AIDS have been observed, and, in every case, disease progression was associated with increased chronic T cell immune activation and inflammation [37,38,39,40].

Results

Conclusion