Abnormal Levels of Some Biomarkers of Immune Activation Despite Very Early Treatment of Human Immunodeficiency Virus

Abstract

Background: Despite early antiretroviral therapy (ART), ART-suppressed people with human immunodeficiency virus (HIV) (PWH) remain at higher risk for infections and infection-related cancers than the general population. The immunologic pathways that remain abnormal in this setting, potentially contributing to these complications, are unclear.

Methods: ART-suppressed PWH and HIV-negative controls, all cytomegalovirus seropositive and enriched for HIV risk factors, were sampled from an influenza vaccine responsiveness study. PWH were stratified by timing of ART initiation (within 6 months of infection [early ART] vs later) and nadir CD4+ T-cell count among later initiators. Between-group differences in kynurenine-tryptophan (KT) ratio, interferon-inducible protein 10, soluble CD14 and CD163, soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor were assessed after confounder adjustment.

Results: Most participants (92%) were male, reflecting the demographics of early-ART initiators in San Francisco. Most biomarkers were higher among later-ART initiators. Participants in the early-ART group achieved near-normal soluble tumor necrosis factor receptor 2, interleukin 6, and soluble urokinase plasminogen activator receptor levels, but substantially higher KT ratio than those without HIV after confounder adjustment (P = .008). Soluble CD14, soluble CD163, and interferon-inducible protein 10 trended similarly.

Conclusions: While early-ART initiators restore near-normal levels of many inflammatory markers, the kynurenine pathway of tryptophan catabolism remains abnormally high. Because this pathway confers adaptive immune defects and predicts tuberculosis and cancer progression, this it may contribute to persistent risks of these complications in this setting.

Keywords: 3-dioxygenase-1; HIV; IP-10; antiretroviral therapy; immune activation; indoleamine 2; inflammation; kynurenine; sCD14; sCD163; tryptophan.

Figure 1.

Inflammatory biomarkers by human immunodeficiency virus (HIV) status and timing of prior antiretroviral therapy (ART) initiation. Plasma biomarker levels are compared between HIV-uninfected controls (n = 41) and ART-suppressed people with HIV, stratified by timing of prior ART initiation: early ART (within 6 months of infection; n = 34) or later ART stratified by nadir CD4⁺ T-cell count (>350/μL [n = 32], 200–350/μL [n = 43], or <200/μL [n = 55]). The kynurenine-tryptophan (KT) ratio is the ratio of the kynurenine level (in nanomoles per liter) to the tryptophan level (in micromoles per liter). P for trend reflects an unadjusted nonparametric test of trend across all ordered groups from HIV negative to CD4⁺ T-cell nadir <200/μL, and the P value between early-ART participants and HIV-uninfected controls reflects a Wilcoxon rank sum test. Abbreviations: IL-6, interleukin 6; IP-10, interferon-inducible protein 10; sCD14, soluble CD14; sCD163, soluble CD163; sTNFR2, soluble tumor necrosis factor receptor 2; suPAR, soluble urokinase plasminogen activation receptor.

Figure 2.

Adjusted difference between early antiretroviral therapy (ART) and human immunodeficiency virus (HIV)–uninfected participants. The mean fold difference in plasma biomarkers between early-ART and HIV-uninfected participants is plotted after normalization to the interquartile range (IQR; in the HIV-uninfected group) and after adjustment for the indicated confounders. Mean fold differences are denoted by circles, with bars spanning 95% confidence intervals. The vertical dotted line reflects a relative fold change of 1.0 (ie, no difference between early-ART and HIV-uninfected groups). Abbreviations: EFV, efavirenz; IL-6, interleukin 6; IP-10, interferon-inducible protein 10; KT, kynurenine-tryptophan; MSM, men who have sex with men; sCD14, soluble CD14; sCD163, soluble CD163; sTNFR2, soluble tumor necrosis factor receptor 2; suPAR, soluble urokinase plasminogen activation receptor.