title: Shift in monocyte apoptosis with increasing viral load and change in apoptosis-related ISG/Bcl2 family gene expression in chronically HIV-1-infected subjects.
abstract: Although monocytes and macrophages are targets of HIV-1-mediated immunopathology, the impact of high viremia on activation-induced monocyte apoptosis relative to monocyte and macrophage activation changes remains undetermined. In this study, we determined constitutive and oxidative stress-induced monocyte apoptosis in uninfected and HIV(+) individuals across a spectrum of viral loads (n = 35; range, 2,243 to 1,355,998 HIV-1 RNA copies/ml) and CD4 counts (range, 26 to 801 cells/mm(3)). Both constitutive apoptosis and oxidative stress-induced apoptosis were positively associated with viral load and negatively associated with CD4, with an elevation in apoptosis occurring in patients with more than 40,000 (4.6 log) copies/ml. As expected, expression of Rb1 and interferon-stimulated genes (ISGs), plasma soluble CD163 (sCD163) concentration, and the proportion of CD14(++) CD16(+) intermediate monocytes were elevated in viremic patients compared to those in uninfected controls. Although CD14(++) CD16(+) frequencies, sCD14, sCD163, and most ISG expression were not directly associated with a change in apoptosis, sCD14 and ISG expression showed an association with increasing viral load. Multivariable analysis of clinical values and monocyte gene expression identified changes in IFI27, IFITM2, Rb1, and Bcl2 expression as determinants of constitutive apoptosis (P = 3.77 × 10(-5); adjusted R(2) = 0.5983), while changes in viral load, IFITM2, Rb1, and Bax expression were determinants of oxidative stress-induced apoptosis (P = 5.59 × 10(-5); adjusted R(2) = 0.5996). Our data demonstrate differential activation states in monocytes between levels of viremia in association with differences in apoptosis that may contribute to greater monocyte turnover with high viremia.
  
  
  OBJECTIVE
  This study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low- versus high-level viremic HIV-1 patients, suggesting a shift in apoptosis regulation that may be associated with disease state. Using single and multivariable analysis of monocyte activation parameters and gene expression, we supported the hypothesis that monocyte apoptosis in HIV disease is a reflection of viremia and activation state with contributions from gene expression changes within the ISG and Bcl2 gene families. Understanding monocyte apoptosis response may inform HIV immunopathogenesis, retention of infected macrophages, and monocyte turnover in low- or high-viral-load states.
authors.affiliation: The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, Pennsylvania, USA University of Pennsylvania Perelman School of Medicine, Department of Microbiology, Philadelphia, Pennsylvania, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Patro
authors.affiliation: The Wistar Institute, Center for Systems and Computational Biology, Philadelphia, Pennsylvania, USA.
authors.forename: Sharmistha
authors.initials: S
authors.lastname: Pal
authors.affiliation: The Wistar Institute, Center for Systems and Computational Biology, Philadelphia, Pennsylvania, USA.
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Bi
authors.affiliation: UPENN-Presbyterian Medical Center, Philadelphia, Pennsylvania, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lynn
authors.affiliation: Philadelphia FIGHT, The Jonathan Lax Treatment Center, Philadelphia, Pennsylvania, USA.
authors.forename: Karam C
authors.initials: KC
authors.lastname: Mounzer
authors.affiliation: UPENN-Presbyterian Medical Center, Philadelphia, Pennsylvania, USA.
authors.forename: Jay R
authors.initials: JR
authors.lastname: Kostman
authors.affiliation: The Wistar Institute, Center for Systems and Computational Biology, Philadelphia, Pennsylvania, USA.
authors.forename: Ramana V
authors.initials: RV
authors.lastname: Davuluri
authors.affiliation: The Wistar Institute, HIV Immunopathogenesis Laboratory, Philadelphia, Pennsylvania, USA Montaner@wistar.org.
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
mesh_terms: D000328:Adult; D000369:Aged, 80 and over; D017209:Apoptosis; D002908:Chronic Disease; D005260:Female; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology* / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D016160:Retinoblastoma Protein / Q000096:biosynthesis; D019562:Viral Load; D055815:Young Adult
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein