title: Impaired CD4 T cell memory response to Streptococcus pneumoniae precedes CD4 T cell depletion in HIV-infected Malawian adults.
abstract: OBJECTIVE
  Invasive pneumococcal disease (IPD) is a leading cause of morbidity and mortality in HIV-infected African adults. CD4 T cell depletion may partially explain this high disease burden but those with relatively preserved T cell numbers are still at increased risk of IPD. This study evaluated the extent of pneumococcal-specific T cell memory dysfunction in asymptomatic HIV infection early on in the evolution of the disease.
  
  
  METHODS
  Peripheral blood mononuclear cells were isolated from asymptomatic HIV-infected and HIV-uninfected Malawian adults and stained to characterize the underlying degree of CD4 T cell immune activation, senescence and regulation. Pneumococcal-specific T cell proliferation, IFN-γ, IL-17 production and CD154 expression was assessed using flow cytometry and ELISpot.
  
  
  RESULTS
  We find that in asymptomatic HIV-infected Malawian adults, there is considerable immune disruption with an increase in activated and senescent CD4+CD38+PD-1+ and CD4+CD25(high)Foxp3+ Treg cells. In the context of high pneumococcal exposure and therefore immune stimulation, show a failure in pneumococcal-specific memory T cell proliferation, skewing of T cell cytokine production with preservation of interleukin-17 but decreased interferon-gamma responses, and failure of activated T cells to express the co-stimulatory molecule CD154.
  
  
  CONCLUSIONS
  Asymptomatic HIV-infected Malawian adults show early signs of pneumococcal- specific immune dysregulation with a shift in the balance of CD4 memory, T helper 17 cells and Treg. Together these data offer a mechanistic understanding of how antigen-specific T cell dysfunction occurs prior to T cell depletion and may explain the early susceptibility to IPD in those with relatively preserved CD4 T cell numbers.
authors: Malawi-Liverpool-Wellcome Trust Clinical Research Programme, University of Malawi College of Medicine, Blantyre, Malawi. sarah.glennie@liverpool.ac.uk
authors: Sarah J
authors: SJ
authors: Glennie
authors: Enoch
authors: E
authors: Sepako
authors: David
authors: D
authors: Mzinza
authors: Visopo
authors: V
authors: Harawa
authors: David J C
authors: DJ
authors: Miles
authors: Kondwani C
authors: KC
authors: Jambo
authors: Stephen B
authors: SB
authors: Gordon
authors: Neil A
authors: NA
authors: Williams
authors: Robert S
authors: RS
authors: Heyderman
mesh_terms: D000293:Adolescent; D000328:Adult; D058345:Asymptomatic Infections; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D023201:CD40 Ligand / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000378:metabolism; D008295:Malawi; D008297:Male; D008875:Middle Aged; D013045:Species Specificity; D013296:Streptococcus pneumoniae / Q000276:immunology* / Q000472:pathogenicity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015854:Up-Regulation / Q000276:immunology; D055815:Young Adult
chemical_list: D020381:Interleukin-17; D023201:CD40 Ligand; D007371:Interferon-gamma