Effects of Tobacco Usage and Antiretroviral Therapy on Biomarkers of Systemic Immune Activation in HIV-Infected Participants

Abstract

Like HIV infection, smoking, which is common among HIV-infected persons, is associated with chronic, systemic inflammation. However, the possible augmentative effects of HIV infection and smoking and other types of tobacco usage on indices of systemic inflammation and the impact of combination antiretroviral therapy (cART) thereon remain largely unexplored and represent the focus of the current study. Of the total number of HIV-infected persons recruited to the study (n = 199), 100 were categorised as pre-cART and 99 as virally suppressed (HIV viral load < 40 copies/mL). According to serum cotinine levels, 144 and 55 participants were categorised as nonusers and users of tobacco, respectively. In addition to cytokines (IL-6, IL-8, and TNF-α) and chemokines (IP-10, MIG, IL-8, MCP-1, and RANTES), other biomarkers of systemic inflammation included C-reactive protein (CRP), β2-microglobulin, and those of neutrophil activation [ICAM-1, L-selectin, matrix metalloproteinase-9 (MMP-9)], microbial translocation (soluble CD14, LPS-binding protein), and oxidative stress (cyclophilin A, surfactant D). These were measured using multiplex bead array, ELISA, and immunonephelometric procedures. Viral suppression was associated with significant decreases in the levels of most of the biomarkers tested (P < 0.0037-0.0008), with the exceptions of CRP, cyclophilin A, and MMP-9. With respect to tobacco usage, irrespective of cART status, circulating levels of β2-microglobulin, cyclophilin A, and RANTES were significantly elevated (P < 0.042-0.012) in users vs nonusers. Additional analysis of the groups of tobacco users and nonusers according to cART status revealed high levels of RANTES in pre-cART/tobacco users relative to the three other subgroups (P < 0.004-0.0001), while more modest increases in cyclophilin A and MMP-9 (P < 0.019-0.027) were observed in comparison with the cART/tobacco user subgroup. Notwithstanding the efficacy of cART in attenuating HIV-associated, chronic systemic inflammation, the current study has identified RANTES as being significantly and seemingly selectively increased in those with active HIV infection who use tobacco, a mechanism which may underpin augmentative proinflammatory activity.

Extracellular Vesicles in Smoking-Mediated HIV Pathogenesis and their Potential Role in Biomarker Discovery and Therapeutic Interventions

“…In addition, Steel at el. have suggested that the chemokine RANTES could be one of the potential candidate biomarkers, which was elevated in their study with HIV positive smokers [128]. Our studies have also demonstrated that these agents are also highly packaged in EVs in the presence of HIV and smoking.…”

“…The potential of EVs is already under investigation in terms of biomarker identification, diagnosis, and prognosis of various conditions, and as therapeutic carriers of drugs in the periphery as well as in the CNS. Our studies and others have postulated the prospect of IL-6, RANTES, soluble CD14, and properdin being potential biomarkers for tobacco-enhanced HIV-pathogenesis [37,49,128,129,[131][132][133][134]. Whether they could be used in actual therapeutic settings will require further study.…”

“…These findings suggest that: a) EVs can potentially be used as a biomarker for smoking-mediated HIV pathogenesis and b) modulating EV-mediated HIV pathogenesis has potential for therapeutic intervention. Several other studies are also looking at potential biomarkers to indicate the possible association between HIV and tobacco smoking, as well as to predict the development of non-AIDS-related illnesses in HIV positive smokers [128][129][130]. Further, Il-6 stands out as a pro-inflammatory cytokine, which is elevated in HIV smokers [131].…”

“…In addition, a few possible markers, IL-6, RANTES, soluble CD14, and properdin have been identified within EVs isolated from the plasma of HIV smokers [37,49,128,129,[131][132][133][134]. However, further studies are warranted to establish their true potential as biomarkers of smoking-induced HIV pathogenesis.…”

A Cross-Sectional Analysis of Tobacco Use and Concurrent Alcohol and Substance Use Among Patients Living with HIV/HCV Co-infection: Findings from a Large Urban Tertiary Center

“…The existing evidence indicates that tobacco use has adverse health effects on almost all parts of the human body (National Center for Chronic Disease Prevention and Health Promotion (US), 2010, 2014), yet 14% (34.2 million) of adults ≥ 18 years old (16% males; 12% females) were current cigarette smokers in 2018 (Creamer et al, 2019). Thus, while it has been established that tobacco use causes chronic diseases such as cardiovascular diseases (CVD), cancer, and chronic obstructive pulmonary disease (COPD) (National Center for Chronic Disease Prevention and Health Promotion (US), 2010, 2014), increasing evidence indicates that it worsens disease progression of several infectious diseases-in particular human immunodeficiency virus (HIV) and hepatitis C virus (HCV) (Bean, Richey, Williams, Wahlquist, & Kilby, 2016;Helleberg et al, 2013;Nahvi & Cooperman, 2009;Tesoriero, Gieryic, Carrascal, & Lavigne, 2010).…”