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

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.

Making a Monkey out of Human Immunodeficiency Virus/Simian Immunodeficiency Virus Pathogenesis: Immune Cell Depletion Experiments as a Tool to Understand the Immune Correlates of Protection and Pathogenicity in HIV Infection

“…The innate cellular effectors recognize invading organisms via pattern recognition receptors, allowing them to distinguish microorganisms and damaged cells from healthy cells [ 151 ]. Meanwhile, anti-HIV antibodies, and sometimes HIV particles, initiate the “classical pathway” of complement activation [ 152 , 153 ]. The complement system does not mediate protection against HIV-infected cells [ 88 ], although it may be critical during acute viral replication [ 87 ].…”

Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys

“…Multiple virally-induced mechanisms lead to the depletion of CD4 + T-cells 4 , including death of infected cells through the action of HIV/SIV-specific CD8 + T-cells 5 , cytolysis induced by virus release 6 and programmed cell death 7 , 8 . However, most of CD4 + T-cells are not HIV/SIV-infected 9 and other mechanisms are involved: (i) increased apoptosis of uninfected cells exposed to viral antigens 10 , 11 , (ii) activation-induced cell death 12 , (iii) pyroptosis in cells undergoing abortive infection 13 , and (iv) destruction of cells trapped in neutrophil extracellular traps induced by HIV/SIV infection 14 , 15 . CD4 + T-cell depletion is thus central to HIV/SIV infection, and, despite the unfolding of antiretroviral therapy (ART), CD4 + T-cells are not entirely restored in people living with HIV (PWH) receiving ART 16 .…”

Aging dysregulates neutrophil extracellular trap formation in response to HIV in blood and genital tissues

“…However, neutrophil responses have shown a controversial role in HIV infection. In chronic HIV/SIV infection, detrimental effects of NETs have been reported, such as the destruction of immune cells, inflammation and tissue damage that would contribute to the pathology observed in chronic infection ( 22 , 23 ). In addition, in the context of genital inflammation and STIs, neutrophil-derived molecules in cervico-vaginal secretions were associated with increased risk of HIV acquisition ( 24 – 26 ).…”