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. 2015 Jan;89(1):799-810.
doi: 10.1128/JVI.02382-14. Epub 2014 Oct 29.

Shift in monocyte apoptosis with increasing viral load and change in apoptosis-related ISG/Bcl2 family gene expression in chronically HIV-1-infected subjects

Sean C Patro  1 , Sharmistha Pal  2 , Yingtao Bi  2 , Kenneth Lynn  3 , Karam C Mounzer  4 , Jay R Kostman  3 , Ramana V Davuluri  2 , Luis J Montaner  5
Affiliations

Shift in monocyte apoptosis with increasing viral load and change in apoptosis-related ISG/Bcl2 family gene expression in chronically HIV-1-infected subjects

Sean C Patro et al. J Virol. 2015 Jan.

Erratum in

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.

Importance: 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.

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Figures

FIG 1
FIG 1
Monocyte apoptosis characterization. Representative 7-AAD/caspase-3 dot plots of purified monocytes from uninfected and HIV+ (14,000 and 439,508 copies/ml) patients are shown. Plots represent overnight constitutive apoptosis (first row) and oxidative stress induced apoptosis (20 μM CdCl2) (second row).
FIG 2
FIG 2
Monocyte apoptosis is elevated in patients above 40,000 copies/ml and associated with viral load and CD4 T cell count. (A) Groupwise comparison of constitutive (left) and induced (right) apoptosis in HIV− versus HIV+ individuals and HIV+ patients below versus above 40,000 (log10 4.6) copies/ml. (B and C) Spearman ranked correlation of viral load (B) and CD4 count (C) versus monocyte apoptosis levels in HIV+ patients. The line on the y axis represents the median constitutive (8.48%) and induced (14.82%) apoptosis levels of the HIV− group. Groupwise comparison displays median and interquartile range using the Mann-Whitney test (two tailed), with a P value of <0.05 considered significant. Spearman (two tailed) rho and P values are displayed.
FIG 3
FIG 3
Monocyte/macrophage activation in HIV+ patient cohort. (A and B) Groupwise comparison of percentage of intermediate CD14++ CD16+ monocytes (left), plasma sCD14 (middle), and plasma sCD163 (right) in HIV− versus HIV+ individuals (A) and HIV+ patients below versus above 40,000 (log10 4.6) copies/ml (B). (C and D) Spearman ranked correlation of viral load (C) and induced apoptosis (D) versus monocyte/macrophage activation metrics. Groupwise comparison displays median, interquartile range (box), and range (whiskers) using the Mann-Whitney test (two-tailed), with a P value of <0.05 considered significant. Spearman (two tailed) rho and P values are displayed.
FIG 4
FIG 4
Monocyte ISG12 family expression is elevated in patients above 40,000 copies/ml and associated with viral load. (A) Groupwise comparison of IFI6, IFI27, and IFITM2 gene expression in HIV+ patients below versus above 40,000 (log10 4.6) copies/ml. (B) Spearman ranked correlation of viral load versus monocyte gene expression. Groupwise comparison displays median, interquartile range (box), and range (whiskers) using the Mann-Whitney test (two tailed), with a P value of <0.05 considered significant. Spearman (two tailed) rho and P values are displayed.
FIG 5
FIG 5
Gene expression correlation of p53, Bcl2, and ISG family genes in monocytes of HIV+ donors. Shown is a Spearman ranked correlation matrix of clinical parameters (brown), p53 (pink), Bcl2 (blue), and ISG (green) family genes, as well as constitutive and induced apoptosis (purple). The results for the Spearman test (two tailed, unadjusted), with a P value of <0.05 considered significant (bold red type), and Spearman rho are displayed (n = 30).
FIG 6
FIG 6
Multivariate analysis of monocyte apoptosis in HIV-1 viremic patients. Shown are the top models generated showing fitted versus observed constitutive (A) and induced (B) apoptosis by multivariate stepwise regression of clinical parameters and apoptosis gene expression.
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