Strategies for serum chemokine/cytokine assessment as biomarkers of therapeutic response in HCV patients as a prototype to monitor immunotherapy of infectious diseases.
In this study, strategies for serum biomarker assessment were developed for therapeutic monitoring of HCV patients. For this purpose, serum chemokine/cytokine levels were measured by cytometric-bead-array in HCV patients, categorized according to immunotherapy response as: non-responder/NR, relapser/REL and sustained-virologic-responder/SVR. The results demonstrated an overall increase of serum chemokine/cytokine levels in HCV patients. In general, therapeutic failure was associated with presence of a predominant baseline proinflammatory pattern with enhanced CCL5/RANTES, IFN-α, IFN-γ along with decreased IL-10 levels in NR and increased IL-6 and TNF in REL. SVR displayed lower baseline proinflammatory status with decreased CXCL8/IL-8, IL-12 and IL-17 levels. The inability to uphold IFN-α levels during immunotherapy was characteristic of NR. Serum chemokine/cytokine signatures further support the deleterious effect of proinflammatory baseline status and the critical role of increased/persistent IFN-α levels to guarantee the sustained virologic response. The prominent baseline proinflammatory milieu observed in NR and REL yielded a restricted biomarker network with small number of neighborhood connections, whereas SVR displayed a network with integrated cytokine connectivity. Noteworthy was that SVR presented a shift towards a proinflammatory pattern upon immunotherapy, assuming a pattern similar to that observed in NR and REL at baseline. Moreover, the immunotherapy guided REL towards a profile similar to SVR at baseline. Analysis of baseline-fold changes during treatment pointed out IFN-α and TNF as high-performance biomarkers to monitor immunotherapy outcome. This knowledge may contribute for novel insights into the treatment and control of the continuous public health threat posed by HCV infection worldwide.
Pós-graduação em Ciências Aplicadas à Saúde do Adulto, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Ambulatório de Hepatites Virais, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, Brazil.
Erica Godinho
EG
Menezes
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Jordana Grazziela Alves
JG
Coelho-Dos-Reis
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Ludmila Melo
LM
Cardoso
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Ágata
Á
Lopes-Ribeiro
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Juan
J
Jonathan-Gonçalves
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Marco Túlio
MT
Porto Gonçalves
Ambulatório de Hepatites Virais, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, Brazil.
Rodrigo Dias
RD
Cambraia
Ambulatório de Hepatites Virais, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, Brazil.
Eric Bassetti
EB
Soares
Pós-graduação em Ciências Aplicadas à Saúde do Adulto, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Ambulatório de Hepatites Virais, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, Brazil; Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Luciana Diniz
LD
Silva
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Vanessa
V
Peruhype-Magalhães
Center for Biologics and Evaluation Research - US Food and Drug Administration, Silver Spring, MD, United States.
Maria
M
Rios
Center for Biologics and Evaluation Research - US Food and Drug Administration, Silver Spring, MD, United States.
Caren
C
Chancey
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil. Electronic address: andreat@cpqrr.fiocruz.br.
Andréa
A
Teixeira-Carvalho
Grupo Integrado de Pesquisa em Biomarcadores, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil.
Olindo Assis
OA
Martins-Filho
Pós-graduação em Ciências Aplicadas à Saúde do Adulto, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil; Ambulatório de Hepatites Virais, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, Brazil; Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Rosângela
R
Teixeira
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D054316:Biomarkers, Pharmacological / Q000097:blood; D018925:Chemokines / Q000097:blood*; D016207:Cytokines / Q000097:blood*; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D019698:Hepatitis C, Chronic / Q000097:blood / Q000628:therapy*; D006801:Humans; D007167:Immunotherapy; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D018664:Interleukin-12 / Q000097:blood; D020381:Interleukin-17 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000627:therapeutic use; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
D000998:Antiviral Agents; D054316:Biomarkers, Pharmacological; C508606:CXCL8 protein, human; D018925:Chemokines; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D020381:Interleukin-17; D016209:Interleukin-8; D011994:Recombinant Proteins; D018664:Interleukin-12; D011092:Polyethylene Glycols; C417083:peginterferon alfa-2b
Biomarkers; Chemokines; Cytokines; HCV; IFN-α