Date Published: February 1, 2012
Publisher: BioMed Central
Author(s): Maude Loignon, Hélène Brodeur, Sonia Deschênes, Denis Phaneuf , Pangala V Bhat, Emil Toma.
Several lines of evidence suggest that retinoids (retinol-ROL or vitamin A, and its active metabolites, retinoic acids-RAs) play important pathogenic roles in HIV infection and combination antiretroviral therapy (cART)-related events. We previously reported that antiretrovirals alter RAs synthesis in vitro. We hypothesised that in vivo serum retinoid concentrations are affected by both cART and HIV infection. This might explain several clinical and laboratory abnormalities reported in HIV-infected patients receiving cART.
The effects of optimal cART and chronic HIV on serum retinoids were firstly assessed longitudinally in 10 HIV-infected adults (group1 = G1): twice while on optimal cART (first, during long-term and second, during short term cART) and twice during 2 cART interruptions when HIV viral load (VL) was detectable. Retinoid concentrations during optimal long term cART in G1 were compared with cross-sectional results from 12 patients (G2) with suboptimal cART (detectable VL) and from 28 healthy adults (G3). Serum retinoids were measured by HPLC with ultraviolet detection. Retinoid concentrations were correlated with VL, CD4+ T- cell count and percentages, CD8+38+ fluorescence, triglycerides, cholesterol and C-peptide serum levels.
During optimal cART, G1 participants had drastically reduced RAs (0.5 ± 0.3 μg/dL; P < 0.01) but the highest ROL (82 ± 3.0 μg/dL) concentrations. During cART interruptions in these patients, RAs slightly increased whereas ROL levels diminished significantly (P < 0.05). G3 had the highest RAs levels (7.2 ± 1.1 μg/dL) and serum ROL comparable to values in North Americans. Serum ROL was decreased in G2 (37.7 ± 3.2 μg/dL; P < 0.01). No correlations were noted between RA and ROL levels or between retinoid concentrations and CD4+ T- cell count, CD8+38+ fluorescence, VL. ROL correlated with triglycerides and cholesterol in G1 (rs = 0.8; P = 0.01). Serum RAs levels are significantly diminished by cART, whereas ROL concentrations significantly decreased during uncontrolled HIV infection but augmented with optimal cART. These alterations in retinoid concentrations may affect the expression of retinoid-responsive genes involved in metabolic, hormonal and immune processes and be responsible for some adverse events observed in HIV-infected persons treated with antiretrovirals. Further studies should assess concomitant serum and intracellular retinoid levels in different clinical situations in larger, homogenous populations.
Retinoids (retinol-ROL- or vitamin A, and its main active metabolites, retinoic acids-RAs) play key roles in multiple human processes [1-3]. ROL is reversibly oxidized intracellularly to retinal by alcohol and short-chain dehydrogenases, whereas retinal is irreversibly oxidized by cytosolic retinal aldehyde dehydrogenases (RALDHs) to RAs, mainly all-trans RA and 9-cis RA [1-3]. Intracellular concentrations of RAs are tightly regulated by synthesizing and catabolizing enzymes and by their binding to cytosol RAs-binding proteins (CRABPs) [2,4]. RAs enter the nucleus, bind and activate nuclear RAs receptors (RARs) or/and retinoid X receptors (RXRs) [3-5]. All-trans RA is the physiological ligand for RAR, whereas 9-cis RA is a high-affinity ligand, in vitro, for RXRs and for RAR [4,5]. However, in vivo, biological activity of 9-cis-RA is not firmly established [3-5]. Once activated by their ligands, these nuclear receptors (ligand-activated transcription factors) bind to RA response elements (RAREs) in the promoter/enhancer of a multitude of genes involved in lipid, glucose and hormonal metabolism, innate and adaptive immunity [1-6]. RXRs also form heterodimers with other nuclear receptors acting as transcription factors for other multiple genes involved in metabolic, hormonal and immune processes [4-9]. Responses in gene expression depend on intracellular RAs concentrations [4,5,9]. Alteration of retinoid concentrations could have, therefore, multiple consequences.
Baseline descriptors are presented in Table 1.
This work provides evidence that serum retinoid concentrations are affected in HIV-infected adults and that both cART and HIV infection are contributing factors. An optimal cART and, to a lesser degree, a suboptimal cART, drastically diminished serum RAs concentrations in HIV-infected adults in comparison to healthy volunteers. This effect was more pronounced and statistically significant in patients with intensified and prolonged optimal cART. Longitudinal assessments in these patients while on or off cART did not show significant changes. This could be due to the low number of participants, great interindividual variability and mostly to the different duration of ON1 versus ON2 and OFF1 versus OFF2. However, if we look at the 75% percentile we see the same “pattern”: RA levels increase during cART interruptions and diminish when cART is re-initiated. Decreased serum RA concentrations during cART is probably the result of altered intracellular retinoid metabolism by cART. We previously demonstrated that some antiretrovirals increase in vitro activity of RALDH1 and, consequently, RAs synthesis . Moreover, one protease inhibitor, indinavir, also augmented RALDH1 mRNA expression . In vivo, such antiretrovirals might also affect intracellular RALDH1, and increase intracellular RAs concentrations especially in those tissues actively involved in retinoid metabolism, like adipose tissue, in which they penetrate, and accumulate [24,25]. However, not all PIs have the same effect since they enter and accumulate differently in different tissues and have different intracellular localizations [21,25,26]. Moreover, as it was recently reported, adipose tissue influences tissue distribution of carotenoids  and certainly of RAs . Heightened RAs concentrations in different tissues  enhance the expression of various P450 CYP enzymes such as CYP 26A1, CYP 26B1 and CYP 26C1, resulting in increased RAs catabolism [10,27]. Of note, these CYP enzymes are different than those affected by PIs. Furthermore, elevated intracellular RAs concentrations have a negative feedback action and reduce their own synthesis by lowering RALDH1 expression . Therefore, it is likely that the low serum RAs concentrations in patients with optimal cART could be due to increased RAs catabolism and feedback inhibition of their synthesis that followed increases in their intracellular concentration when cART was initiated. In order to document this assumption, concomitant measurements of serum and tissue RAs concentrations are necessary. This was not possible when this study was undertaken because our technique was not suited, at that time, for tissue samples processing. Altered retinoid metabolism could have multiple consequences by affecting RAs-dependent genes involved in metabolic, hormonal and immune processes [4,6,1,23] and may explain some reported HIV- and cART-related metabolic and hormonal abnormalities .
The authors declare that they have no competing interests.
The authors’ contributions were as follows-ML: elaboration of patient’s consent forms and information for participants, healthy controls enrolment, study design, HPLC analysis, data collection and interpretation, figures and manuscript preparation; HB: HPLC technique adaptation for human samples, serum analysis, data interpretation and manuscript preparation; SD-serum analysis, data interpretation, manuscript preparation; DP: study design, provision of significant clinical advice and manuscript preparation; PVB: overall laboratory supervision, HPLC technique development, design of the study, data interpretation and manuscript preparation; ET: study design and coordination, patients enrolment and follow-up, statistical analysis and data interpretation, manuscript preparation.