title: 'Modeling' relationships among HIV-1 replication, immune activation and CD4+ T-cell losses using adjusted correlative analyses.
abstract: OBJECTIVE
  To model the relationships among HIV-1 replication, immune activation and CD4+ T-cell losses in HIV-1 infection.
  
  
  METHODS
  Cross-sectional analysis of baseline data from the Viral Activation by Transfusion Study. Comparisons of unadjusted and adjusted correlative analyses to establish models for mechanisms of cell loss in AIDS.
  
  
  RESULTS
  Using these analyses, significant correlations were found among plasma levels of tumor necrosis factor alpha (TNFalpha) and its type two receptor (TNFrII), interleukin-6 (IL-6), beta2-microglobulin, expression of CD38 and HLA-DR on CD8+ T lymphocytes and plasma levels of HIV-1 RNA. When correlations among these indices were adjusted for possible intermediary correlations, the relationship between HIV-1 RNA levels and all plasma markers of immune activation could be accounted for by the correlation between plasma HIV-1 RNA and plasma TNFrII levels. In addition, the negative correlations that both HIV-1 RNA levels and TNFrII levels had with CD4+ T-cell counts were partially accounted for by the correlations of HIV-1 RNA and TNFrII with CD38 expression on CD8+ T cells. In persons with advanced disease (CD4+ T cells < 50 x 10(6)/l) IL-6 levels were inversely correlated with CD4+ T-cell counts.
  
  
  CONCLUSIONS
  This analysis is consistent with a model wherein HIV-1 replication induces TNFalpha expression that induces multiple other indices of immune activation. In this model, HIV-1 replication and TNFalpha expression induce CD4+ T-cell losses at least in part through mechanisms reflected in heightened CD38 expression.
authors.affiliation: Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. Lederman.Michael@clevelandactu.org
authors.forename: M M
authors.initials: MM
authors.lastname: Lederman
authors.forename: L A
authors.initials: LA
authors.lastname: Kalish
authors.forename: D
authors.initials: D
authors.lastname: Asmuth
authors.forename: E
authors.initials: E
authors.lastname: Fiebig
authors.forename: M
authors.initials: M
authors.lastname: Mileno
authors.forename: M P
authors.initials: MP
authors.lastname: Busch
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000328:Adult; D015703:Antigens, CD / Q000097:blood; D000943:Antigens, Differentiation / Q000378:metabolism; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology* / Q000502:physiology*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009244:NAD+ Nucleosidase / Q000378:metabolism; D012367:RNA, Viral / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D012367:RNA, Viral; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1