Untreated HIV versus non-HIV-infected controls
Persistent metabolic changes in HIV-infected patients during the first year of combination antiretroviral therapy
Abstract
The HIV-human metabolic relationship is a complex interaction convoluted even more by antiretroviral therapy (cART) and comorbidities. The ability of cART to undo the HIV induced metabolic dysregulation is unclear and under-investigated. Using targeted metabolomics and multiplex immune biomarker analysis, we characterized plasma samples obtained from 18 untreated HIV-1-infected adult patients and compared these to a non-HIV infected (n = 23) control population. The biogenic amine perturbations during an untreated HIV infection implicated altered tryptophan- nitrogen- and muscle metabolism. Furthermore, the lipid profiles of untreated patients were also significantly altered compared to controls. In untreated HIV infection, the sphingomyelins and phospholipids correlated negatively to markers of infection IP-10 and sIL-2R whereas a strong association was found between triglycerides and MCP-1. In a second cohort, we characterized plasma samples obtained from 28 HIV-1-infected adult patients before and 12 months after the start of cART, to investigate the immune-metabolic changes associated with cART. The identified altered immune-metabolic pathways of an untreated HIV infection showed minimal change after 12 months of cART. In conclusion, 12 months of cART impacts only mildly on the metabolic dysregulation underlying an untreated HIV infection and provide insights into the comorbidities present in virally suppressed HIV patients.
Introduction
The interaction of the Human immunodeficiency virus (HIV) with its host is a complex process with a growing body of literature revealing the capacity of HIV to induce a plethora of metabolic changes in the human body1,2,3,4,5. Hypertriglyceridemia was identified as one of the first metabolic consequences of HIV infection6. Since then, studies using Mass Spectrometry (MS) and Nuclear Magnetic Resonance (NMR) applied to biofluids of HIV-infected individuals have confirmed the presence of HIV induced metabolic alterations1,7,8,9. Investigating in vitro models of HIV infection using primary macrophages and CD4+ T-cells had different metabolic outcomes during HIV infection. CD4+ T-cells infected with HIV exhibited increased glucose uptake and upregulated glycolytic intermediates compared to reduced glucose uptake and steady-state glycolytic intermediates in HIV-infected macrophages10. While, in vivo models using rhesus macaques infected with simian immunodeficiency virus (SIV) revealed increased fatty acids, phospholipids, and acyl-carnitines, suggesting an impaired mitochondrial fatty acid oxidation11. Comparatively, serum and plasma derived from HIV infected individuals revealed altered metabolites of lipid and mitochondrial pathways as well as organic acids and fatty acids1,5. Moreover, the saliva from HIV-infected patients versus healthy controls revealed alterations in carbohydrate biosynthesis and degradation2.
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Infection with HIV causes a progressive malfunctioning of the human immune system. HIV infection depletes CD4+ T-cells, while also inducing functionally exhausted CD8+ T-cells and impaired NK cells, leaving the host vulnerable to opportunistic infections12. Furthermore, the metabolic and immunological changes in untreated HIV patients increase the risk of developing comorbidities, including cardiovascular disease (CVD), insulin resistance and HIV-associated neurocognitive disorders (HAND)13,14.The advent of combination antiretroviral therapy (cART) provided an important lifeline for HIV patients, since cART effectively inhibits HIV replication to undetectable levels, while also enabling the restoration of the immune system with increasing CD4+ T-cell counts. Nevertheless, important metabolic-related side-effects of cART are reported in patient populations, mainly lipodystrophy and insulin resistance, which may further predispose virally suppressed patients to increased CVD, diabetes, and kidney damage15,16,17. Also, studies have shown that although cART dramatically decreased the incidence of the most severe clinical phenotype of HAND (HIV associated neurocognitive disorder) – HIV-associated dementia - in virally suppressed patients the milder forms of HAND - asymptomatic neurocognitive impairment and mild neurocognitive disorders- have become more prevalent18,19. One aspect of the pathogenesis of CVD or HAND in successfully treated HIV patients is that while cART effectively suppresses HIV replication and activity, low levels of immune activation are sustained20,21,22. The ability of cART to rectify the HIV-induced metabolic dysregulation is unclear and under-investigated. However, this may be highly relevant since persistent metabolic stress could be an underlying pathogenic mechanism in the comorbidities of untreated HIV patients as well as cART suppressed HIV patients. Robust characterization of the metabolic alterations experienced during HIV infection is needed to determine the effect of cART on these pathways, in cART suppressed HIV patients.To study this, we used comprehensive targeted metabolomics techniques integrated with classical immunological assays and compared changes in plasma of untreated HIV-1 patients to non-HIV infected individuals, and paired plasma of untreated HIV-1 patients at baseline to their plasma after 12 months of cART in the HIV-suppressed state, to assess whether profiles normalized to the situation in healthy individuals or remained perturbed. We found dysregulated biogenic amine and lipid metabolism in untreated HIV-infected patients, conditions that have been independently associated with the pathophysiology of CVD and HAND. After 12 months of cART, metabolic changes were found for some biogenic amines, while the lipid metabolites revealed increasing levels in the virally suppressed patients.
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Results
Untreated HIV versus non-HIV-infected controls
Patient population A
Most of the individuals in both the patient and the control populations listed in Table 1 were male and Caucasians. Mean age did not differ between both groups. The mean CD4+ T-cell count of the HIV-1 patients was 441 × 106 cells/L with an interquartile range (IQR) of 367.5 × 106. The untreated HIV patients had a large heterogeneity in viral load with a median of 1.11 × 105 viral copies and an IQR of 2.64 × 105 especially when taking the minimum and maximum values as listed in Table 1 into account.
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