title: Immune dysfunction and immune restoration disease in HIV patients given highly active antiretroviral therapy.
abstract: BACKGROUND
  Some immune defects caused by HIV infection resolve following treatment with highly active antiretroviral therapy (HAART), but residual immune dysfunction may cause disease. Problems with the regulation of the restored immune system in the first six months of treatment can lead to atypical presentations of mycobacterial, cytomegalovirus (CMV), hepatitis B virus or hepatitis C virus (HCV) disease. We defined these conditions as immune restoration diseases (IRD) and showed that they occur in 30-40% of individuals who begin HAART from low CD4 T cell counts.
  
  
  OBJECTIVE
  Analysis of immune dysregulation in patients who have responded to HAART.
  
  
  METHODS
  Patients with successful immune reconstitution following HAART were selected from a database containing details of all patients managed at Royal Perth Hospital (Western Australia) on the basis a CD4 T cell count <100/microl before HAART and an increase of >4-fold or to >200 CD4 T cells/microl.
  
  
  RESULTS
  Patients who had experienced an IRD demonstrated increased levels of bioavailable IL-6 and increased expression of CCR5 and CCR3 on monocytes and granulocytes, but numbers of gammadeltaT-cells were similar to patients with similar CD4 T cell counts without an IRD. Carriage of HLA-A2, -B44 was associated with a history of CMV retinitis and/or encephalomyelitis as an IRD, but not with IRD initiated by Mycobacterium sp., cutaneous varicella zoster or herpes simplex infections or HCV. We also identified a patient with Graves' thyrotoxicosis and pronounced lymphadenopathy after HAART, and demonstrated that thyroid stimulating hormone receptor antibody production was associated with an increase in serum soluble CD30, suggesting acquired immune dysregulation.
  
  
  CONCLUSIONS
  IRD are associated with persistent immune activation, where differences in genetic profiles suggest that distinct pathological mechanisms are responsible for retinitis/encephalomyelitis IRD. Further studies are important as dysregulated T-cell responses may cause disease later in the course of immune reconstitution.
authors.affiliation: Department of Clinical Immunology and Biochemical Genetics, Royal Perth Hospital, GPO X2213, Perth, WA 6001, Australia. pprice@cyllene.uwa.edu.au
authors.forename: P
authors.initials: P
authors.lastname: Price
authors.forename: N
authors.initials: N
authors.lastname: Mathiot
authors.forename: R
authors.initials: R
authors.lastname: Krueger
authors.forename: S
authors.initials: S
authors.lastname: Stone
authors.forename: N M
authors.initials: NM
authors.lastname: Keane
authors.forename: M A
authors.initials: MA
authors.lastname: French
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000276:immunology*; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D017726:Cytomegalovirus Retinitis / Q000276:immunology; D004679:Encephalomyelitis / Q000276:immunology; D006098:Granulocytes / Q000276:immunology; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D015789:HLA-A2 Antigen / Q000032:analysis; D015235:HLA-B Antigens / Q000032:analysis; D059948:HLA-B44 Antigen; D006801:Humans; D007107:Immune System / Q000187:drug effects; D015850:Interleukin-6 / Q000032:analysis; D018655:Lymphocyte Count; D009000:Monocytes / Q000276:immunology; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology; D054397:Receptors, CCR3; D019713:Receptors, CCR5 / Q000032:analysis; D019707:Receptors, Chemokine / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D019380:Anti-HIV Agents; C515350:CCR3 protein, human; D015789:HLA-A2 Antigen; D015235:HLA-B Antigens; D059948:HLA-B44 Antigen; D015850:Interleukin-6; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054397:Receptors, CCR3; D019713:Receptors, CCR5; D019707:Receptors, Chemokine