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) IMPORTANCEThis study characterized differential monocyte activation, apoptosis, and apoptosis-related gene expression in low-versus highlevel 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.

Preferential Destruction of Interstitial Macrophages over Alveolar Macrophages as a Cause of Pulmonary Disease in Simian Immunodeficiency Virus–Infected Rhesus Macaques

“…In addition, plasma CXCL13 could also be considered since it has been reported to correlate with the level of plasma viral load in HIV-infected cohorts (42), although our study indicated that not all SIV-infected macaques with high viral load exhibited high monocyte turnover, so this is another area of exploration. Patro et al (43) reported that apoptosis of monocytes correlated with HIV plasma levels and while SIV levels did not necessarily correlate with disease progression in our studies using rhesus macaques, monocyte apoptosis could also be considered for its relationship or impact on monocyte turnover. The nonhuman primate model of AIDS is especially amenable to examining these mechanisms and their impact on both populations of lung macrophages via BAL and tissue biopsy and thus provides an important resource for studies about the mechanisms of HIV/AIDS and HANA pathogenesis as well as for defining sites of viral reservoirs necessary to rationally target effective therapies.…”

Role of immune activation in progression to AIDS

“…HIV results in a shift from “classical” CD14++CD16− to “non-classical” CD14+CD16+ and “intermediate” CD14++CD16+ monocytes, which are associated with an inflammatory phenotype [40–42] and greater viremia and/or CD4+ T cell depletion [42, 43]. High expression of the PD1 homologue (PD-1H), which is associated with increased production of TNF, IL-1β, and IL-6, may also contribute to the pro-inflammatory state of these monocytes [44].…”

“…High plasma IP-10, IL-6 and sCD14 all consistently predict increased subsequent morbidity and mortality during ART [42, 43, 60], and high sCD163 levels have been associated with surrogate markers of neurologic and cardiovascular disease (though perhaps not cardiovascular events [61]), as well as all-cause mortality in a recent report [26, 57–59, 62, 63]. As many of these biomarkers of monocyte activation may be increased by smoking and/or alcohol use, many of these associations with morbidity and mortality may be at least in part driven by behavioral risk factors and not HIV itself, though a recent report suggests that these associations persist despite adjustment for behavioral risk factors [64].…”

Gene Expression Profiles of HIV/AIDS Patients with Qi-Yin Deficiency and Dampness-Heat Retention

“…36,37 Family members of BCL can help B cells in patients with HIV/AIDS evade elimination by Fas-mediated cell death. 38,39 In addition, NFKBIA (NF-κB inhibitor α) encodes a protein that blocks NF-κB. 40 After TCM intervention, BCL2A1, NFKBIA, and PTGS2 tended to normalize.…”