BackgroundInjection drug use is a growing major public health concern. Injection drug users (IDUs) have a higher incidence of co-morbidities including HIV, Hepatitis, and other infections. An effective humoral response is critical for optimal homeostasis and protection from infection; however, the impact of injection heroin use on humoral immunity is poorly understood. We hypothesized that IDUs have altered B cell and antibody profiles.Methods and FindingsA comprehensive systems biology-based cross-sectional assessment of 130 peripheral blood B cell flow cytometry- and plasma- based features was performed on HIV-/Hepatitis C-, active heroin IDUs who participated in a syringe exchange program (n = 19) and healthy control subjects (n = 19). The IDU group had substantial polydrug use, with 89% reporting cocaine injection within the preceding month. IDUs exhibited a significant, 2-fold increase in total B cells compared to healthy subjects, which was associated with increased activated B cell subsets. Although plasma total IgG titers were similar between groups, IDUs had significantly higher IgG3 and IgG4, suggestive of chronic B cell activation. Total IgM was also increased in IDUs, as well as HIV Envelope-specific IgM, suggestive of increased HIV exposure. IDUs exhibited numerous features suggestive of systemic inflammation, including significantly increased plasma sCD40L, TNF-α, TGF-α, IL-8, and ceramide metabolites. Machine learning multivariate analysis distilled a set of 10 features that classified samples based on group with absolute accuracy.ConclusionsThese results demonstrate broad alterations in the steady-state humoral profile of IDUs that are associated with increased systemic inflammation. Such dysregulation may impact the ability of IDUs to generate optimal responses to vaccination and infection, or lead to increased risk for inflammation-related co-morbidities, and should be considered when developing immune-based interventions for this growing population.
The primary objective of a preventative HIV vaccine is the induction of a persistent humoral response that mediates sterilizing immunity. Although modest, yet encouraging, a reduction in infections in low-risk individuals was obtained in the RV144 HIV vaccine efficacy trial; for high-risk individuals, including injection drug users (IDU) no substantial reduction in infection has been observed in efficacy trials. The impact of injection drug use on humoral responses is poorly defined, particularly in the context of HIV prevention. Through a cross-sectional assessment of peripheral B cells and plasma antibodies, we have identified substantial alterations in the HIV-/HepC- active heroin IDU population. IDU exhibited significantly increased total B cells compared to healthy subjects, that were associated with significantly increased memory B cells and plasmablasts. Additionally, although plasma total IgG levels were similar between IDU and healthy subjects, IDU had significantly higher titers of IgG3 and IgG4 subclass plasma antibodies. Total IgM plasma antibodies were also increased in IDU. This humoral dysregulation may be the consequence of a pro-inflammatory environment as evident by significantly increased plasma sCD40L in IDU. These results demonstrate extensive differences in the steady-state humoral profile of IDU, which could have the potential to severely influence the quality of the B cell and antibody response, and ultimate efficacy of future HIV vaccine strategies.
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