RESUMO
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in "intermediate" CD14++CD16+ monocytes and an activated subpopulation of CD14+ monocytes. Increases in acute-phase CHIKV envelope protein E2 expression were highest for monocytes and dendritic cells. Serum cytokine measurements confirmed significant acute-phase upregulation of monocyte chemoattractants. Distinct transcriptomic signatures were associated with infection timepoint, as well as convalescent-phase anti-CHIKV antibody titer, acute-phase viremia, and symptom severity. We present a multiscale network that summarizes all observed modulations across cellular and transcriptomic levels and their interactions with clinical outcomes, providing a uniquely global view of the biomolecular landscape of human CHIKV infection.
Assuntos
Febre de Chikungunya/genética , Vírus Chikungunya/genética , Imunidade Inata/genética , Transcriptoma/genética , Adolescente , Animais , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Febre de Chikungunya/transmissão , Febre de Chikungunya/virologia , Vírus Chikungunya/imunologia , Vírus Chikungunya/patogenicidade , Criança , Pré-Escolar , Culicidae/virologia , Citocinas/sangue , Citocinas/genética , Células Dendríticas/imunologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Lactente , Recém-Nascido , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/imunologia , Monócitos/imunologia , Pediatria , Receptores de IgG/genética , Receptores de IgG/imunologia , Análise de Sequência de RNA , Transcriptoma/imunologiaRESUMO
OBJECTIVES: HIV infection is associated with increased prevalence of subclinical coronary plaque. The extent to which such plaque reflects effects of HIV infection or effects of long-term antiretroviral therapy (ART) use remains unclear and was the goal of this analysis. DESIGN AND METHODS: We compared the prevalence and extent of coronary plaque and stenosis between users of specific ART drugs or drug classes using coronary computed tomography (CT) among HIV-infected men in the Multicenter AIDS Cohort Study. To account for time-dependent confounders, including cardiovascular disease risk factors and time-varying reasons for using specific treatments, we conducted fully adjusted logistic and linear models with inverse probability of treatment weighting. RESULTS: There were 618 men who underwent noncontrast coronary CT; 450 also underwent coronary CT angiography. At the time of scanning, 81% had undetectable plasma HIV RNA. In fully adjusted models, cumulative use of zidovudine, abacavir, darunavir, and protease inhibitors as a drug class were inconsistently associated with specific forms of plaque presence or extent. CONCLUSION: Among virally suppressed HIV-infected men with extensive ART exposure, no consistent associations between use of specific ART drugs and both subclinical coronary plaque presence and extent were apparent. Our findings support the hypothesis that, among virally suppressed persons, type of ART used is not in general a major determinant of subclinical coronary plaque risk.