title: Classical and alternative macrophages have impaired function during acute and chronic HIV-1 infection.
abstract: OBJECTIVE
  Three decades after HIV recognition and its association with AIDS development, many advances have emerged - especially related to prevention and treatment. Undoubtedly, the development of Highly Active Antiretroviral Therapy (HAART) dramatically changed the future of the syndrome that we know today. In the present study, we evaluate the impact of Highly Active Antiretroviral Therapy on macrophage function and its relevance to HIV pathogenesis.
  
  
  METHODS
  PBMCs were isolated from blood samples and monocytes (CD14+ cells) were purified. Monocyte-Derived Macrophages (MDMs) were activated on classical (MGM-CSF+IFN-γ) or alternative (MIL-4+IL13) patterns using human recombinant cytokines for six days. After this period, Monocyte-Derived Macrophages were stimulated with TLR2/Dectin-1 or TLR4 agonists and we evaluated the influence of HIV-1 infection and Highly Active Antiretroviral Therapy on the release of cytokines/chemokines by macrophages.
  
  
  RESULTS
  The data were obtained using Monocyte-Derived Macrophages derived from HIV naïve or from patients on regular Highly Active Antiretroviral Therapy. Classically Monocyte-Derived Macrophages obtained from HIV-1 infected patients on Highly Active Antiretroviral Therapy released higher levels of IL-6 and IL-12 even without PAMPs stimuli when compared to control group. On the other hand, alternative Monocyte-Derived Macrophages derived from HIV-1 infected patients on Highly Active Antiretroviral Therapy released lower levels of IL-6, IL-10, TNF-α, IP-10 and RANTES after LPS stimuli when compared to control group. Furthermore, healthy individuals have a complex network of cytokines/chemokines released by Monocyte-Derived Macrophages after PAMP stimuli, which was deeply affected in MDMs obtained from naïve HIV-1 infected patients and only partially restored in MDMs derived from HIV-1 infected patients even on regular Highly Active Antiretroviral Therapy.
  
  
  CONCLUSIONS
  Our therapy protocols were not effective in restoring the functional alterations induced by HIV, especially those found on macrophages. These findings indicate that we still need to develop new approaches and improve the current therapy protocols, focusing on the reestablishment of cellular functions and prevention/treatment of opportunistic infections.
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil.
authors.forename: Leonardo J
authors.initials: LJ
authors.lastname: Galvão-Lima
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil.
authors.forename: Milena S
authors.initials: MS
authors.lastname: Espíndola
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil.
authors.forename: Luana S
authors.initials: LS
authors.lastname: Soares
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil.
authors.forename: Fabiana A
authors.initials: FA
authors.lastname: Zambuzi
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil.
authors.forename: Maira
authors.initials: M
authors.lastname: Cacemiro
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil.
authors.forename: Caroline
authors.initials: C
authors.lastname: Fontanari
authors.affiliation: Universidade de São Paulo, Hospital das Clínicas de Ribeirão Preto, Divisão de Doenças Infecciosas, São Paulo, SP, Brazil.
authors.forename: Valdes R
authors.initials: VR
authors.lastname: Bollela
authors.affiliation: Universidade de São Paulo, Faculdade de Ciências Farmacêuticas, Laboratório de Imunologia e Epigenética, São Paulo, SP, Brazil. Electronic address: frantz@Usp.Br.
authors.forename: Fabiani G
authors.initials: FG
authors.lastname: Frantz
mesh_terms: D000208:Acute Disease; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D016516:CD4-CD8 Ratio; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D016022:Case-Control Studies; D018946:Chemokine CCL5 / Q000378:metabolism; D054357:Chemokine CXCL10 / Q000378:metabolism; D002908:Chronic Disease; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects*; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D019562:Viral Load / Q000187:drug effects
chemical_list: D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D007378:Interleukins; D018950:Lipopolysaccharide Receptors; D014409:Tumor Necrosis Factor-alpha
keywords: HAART; HIV-1; Innate immune response; Macrophages