ABSTRACT

The Acquired Immunodeficiency Syndrome (AIDS), caused by infection with the Human Immunodeficiency Virus Type-1 (HIV), is characterized by profound immunosuppression, particularly of the innate, and T-helper (Th) 1-directed immunity. AIDS causes multisystem dysfunction, including impairment of the hypothalamic-pituitary-adrenal (HPA) axis, a major system coordinating the resting state and the adaptive response to stress. This neuroendocrine axis consists of three components: the hypothalamus, the pituitary gland, and the adrenal cortex with its end-effector molecules, the glucocorticoids. AIDS/HIV influence the HPA axis directly, through modulation of the host immune activity and alterations of the cellular biological pathways via HIV-encoded proteins, as well as indirectly, through immunodeficiency-associated opportunistic infections and various side effects of the therapeutic compounds employed, including those used in the highly active antiretroviral therapy (HAART). In this chapter, the interaction between AIDS/HIV and the HPA axis is reviewed and discussed. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Patients with Acquired Immunodeficiency Syndrome (AIDS), caused by infection with the Human Immunodeficiency Virus Type-1 (HIV), develop profound immunosuppression, particularly of their innate and T-helper (Th) 1-directed cellular immunity (1). These patients may also present with dysfunction of many organ systems, including the hypothalamic-pituitary-adrenal (HPA) axis (2). During the last 25 years, numerous reports have provided evidence for alterations of the HPA axis and its influence on target tissues in HIV-infected patients (Table 1). Indeed, AIDS has been associated with adrenalitis caused by opportunistic infections, adrenal dysfunction secondary to neoplastic infiltration into the adrenal cortices, and changes related to circulating cytokines and other bioactive molecules known to influence functions of the HPA axis (3). Glucocorticoid hormones secreted from the adrenal cortex act as end-effectors of the HPA axis and have strong anti-inflammatory effects (4). Thus, these hormones were considered for reversing HIV-mediated depletion of circulating CD4+ lymphocytes and slowing progression to AIDS, as well as to subside complications associated with HIV infection (5) (Table 2).

Although development of HIV vaccines targeting components of the viral particles is still challenging, establishment and clinical introduction of the highly active antiretroviral therapy (HAART) that employs combinatory use of the three different types of antiretroviral drugs, such as nucleoside and non-nucleoside analogues acting as reverse transcriptase inhibitors, non-peptidic viral protease inhibitors (PIs) and the compounds blocking entry of HIV to CD4+ lymphocytes, efficiently suppress HIV replication in infected patients and have dramatically improved clinical course and life expectancy of AIDS patients (6-9). However, the prolongation of lives with long-term use of the above antiretroviral agents have generated novel morbidities and complications, which influence the patients’ quality of life and add new risk factors for premature death. Central among them is the quite common AIDS-related insulin resistance and lipodystrophy syndrome (ARIRLS), which is characterized by a striking phenotype and marked metabolic disturbances that are reminiscent of Cushing syndrome (10). In agreement with above-indicated clinical background, acquired alterations in the sensitivity of tissues to glucocorticoids were originally hypothesized in AIDS patients, and this concept was further extended to other nuclear receptor (NR) family proteins. In addition, some PIs inhibit the cytochrome p450 enzyme CYP3A4, which is necessary to metabolize glucocorticoids into inactive forms (11). Thus, the pharmacologic action of glucocorticoids used in the AIDS patients treated with these compounds is pronounced due to slowing of their metabolism, and “iatrogenic” Cushing syndrome is subsequently developed in these patients (12).

AIDS patients frequently develop several different types of malignancies, such as lymphoma and Kaposi sarcoma, in part due to profound destruction of host immune system by HIV (13,14). Glucocorticoids are among the central compounds for the treatment of the patients harboring these malignancies (13,15). Glucocorticoids are also pivotal for the treatment of HIV-associated nephropathy, which is observed in about 10% of AIDS patients (16). Use of glucocorticoids is further considered for the patients with HIV-associated tuberculosis and other opportunistic infections as part of the immunoadjuvant therapy (17,18).

In this chapter, we will explain known interactions between HIV infection and the HPA axis, particularly focusing on glucocorticoid hormones. We also present our understanding on some emerging concepts of such interactions, and discuss their possible mechanisms and relevance to HIV pathogenesis.

HPA AXIS AND GLUCOCORTICOID ACTIONS

Humans face unforeseen short- and long-term environmental changes called “stressors”, which can be external (e.g. excessive heat or cold, food deprivation, trauma and invasion by pathogens) or internal (e.g. hurtful memories, splachnic injuries, neoplasia’s) (19-22). To adapt to these changes, humans have the stress-responsive system, which senses such stressors through various peripheral sensory organs, processes them in the central nervous system (CNS), and adjusts the CNS and peripheral organ activities (19-22). The hypothalamic-pituitary-adrenal (HPA) axis with its end-effectors glucocorticoids is one of the two arms of this regulatory system, together with the locus caeruleus/norepinephrine-autonomic system and their end-effectors, norepinephrine and epinephrine (19,21,22). At baseline, activity of the HPA axis and circulating glucocorticoid levels are in a typical diurnal rhythm, reaching their zenith in the early morning and their nadir in the late evening in diurnal animals including humans through input from a circadian rhythm center, the suprachiasmatic nucleus (SCN), and they participate in the maintenance of internal homeostasis (20,23,24). Upon exposure to stressors, the HPA axis is liberated from this regular circadian rhythm, and is strongly activated to modulate many biological activities including those of the CNS, intermediary metabolism, immunity and reproduction via highly elevated circulating glucocorticoids (4,19-25). However, this stress-induced activation of the HPA axis may also exert an array of adverse effects when its response is not properly tailored to the stressful stimuli (25). For example, acute hyper-activation of the HPA axis has been associated with development of post-traumatic stress disorder, while chronic activation of the HPA axis, and consequently prolonged elevation of serum glucocorticoid levels, induce visceral-type obesity and insulin resistance/dyslipidemia, which are represented as metabolic syndrome (19,21-25).

The HPA axis consists of the hypothalamic PVN parvocellular corticotropin-releasing hormone (CRH)- and arginine vasopressin (AVP)-secreting neurons, the corticotrophs of the pituitary gland, and the adrenal gland cortex (3,21-24) (Figure 1A). The PVN neurons release CRH and AVP into the hypophyseal portal system located under the median eminence of the hypothalamus in response to stimulatory signals from higher brain regulatory centers (3,21-24). Secreted CRH and AVP reach the pituitary gland and synergistically stimulate secretion of the adrenocorticotropic hormone (ACTH) from corticotrophs (19,21-24,26). ACTH released into systemic circulation finally stimulates both production and secretion of glucocorticoids (cortisol in humans and corticosterone in rodents) from the zona fasciculata of the adrenal cortex (25). Secreted glucocorticoids modulate activity of virtually all organs and tissues to adjust their functions. In addition, these hormones suppress higher regulatory centers of the HPA axis, the PVN and the pituitary gland, ultimately forming a closed negative feedback loop that aims to reset the activated HPA axis and restore its homeostasis (19).

Figure 1.

The HPA axis and intracellular actions of GR

INTERACTION OF THE HPA AXIS AND HIV INFECTION

GLUCOCORTICOIDS IN THE TREATMENT OF AIDS PATIENTS

GLUCOCORTICOIDS RESISTANCE/HYPERSENSITIVITY ASSOCIATED WITH AIDS PATIENTS

Factors Contributing to the Development of ARIRLS

ANTIRETROVIRAL DRUGS

Protease Inhibitors (PIs)

Possible mechanisms contributing to this characteristic syndrome are listed in Table 3 and summarized in Figure 2. As several previous reports indicated, one of the earlier suggestions was that the syndrome was outcome of adverse effects of antiretroviral drugs including PIs, nucleoside reverse transcriptase inhibitors (NRTIs) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) (147,149). PIs interfere with viral replication by efficiently inhibiting the activity of the viral-encoded protease, which normally digests the Gag-Pol p160 kDa precursor protein, producing several polypeptide fragments with distinct functions (149,150). NRTIs and NNRTIs, on the other hand, inhibit viral replication by suppressing the activity of the reverse transcriptase also encoded by HIV (149). The effects of various antiretroviral drugs on the development of lipodystrophy and metabolic complications are listed in Table 4. Since prototype drugs were significantly associated with the development of ARIRLS, new compounds with less association were subsequently developed.

Figure 2.

Major proposed mechanisms in the genesis of ARIRLS. Three major components, antiretroviral drugs, viral factors and host factors differentially contribute to the development of ARIRLS by respectively modulating adipogenesis, lipogenesis, and tissue insulin action through induction of/responsiveness to inflammatory cytokines, damage to adipocytes (e.g. by mitochondrial toxicity and reactive oxygen species) and/or through modulation of host cellular mechanisms, such as NR (GR, PPAR, PXR and LXR) signaling systems and inhibition/modulation of p450 enzyme activity (such as CYP3A and steroidogenic enzymes). Some changes can also alter tissue glucocorticoid action (glucocorticoid sensitivity) through expression of the GR and/or 11βHSD1 that converts inactive cortisone to active cortisol. As sum of these changes, major manifestations, lipohypertrophy, lipoatrophy and insulin resistance/dyslipidemia are finally developed in which modulation of the glucocorticoid metabolism/signaling system play a significant part. Their specific actions on visceral and subcutaneous fat may contribute to the development of lipohypertrophy and lipoatrophy in different body areas. [from (29,46,147,151)]

Table 3.

Potential Contributing Factors to AIDS-Related Insulin Resistance and Lipodystrophy Syndrome (ARIRLS) Before and After Treatment with Antiretroviral Drugs

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	Before Rx	After Rx
Nonspecific, disease-related
Sickness-related starvation	+	Refeed
Sickness-related change in body composition	Lean body mass loss*	Fat mass gain*
Infection-induced hypercytokinemia	+
Cytokine-induced adipose tissue 11βHSD1 stimulation	+	-
Stress- and starvation-induced hypercortisolism	+	-
Specific, HIV-related
Virally-induced muscle, liver, and fat glucocorticoid hypersensitivity	+	+
Virally-induced adipose tissue PPARγ inhibition	+	+
Virally-induced adipose tissue 11βHSD1 stimulation	+	+
Antiretroviral drug-related
Rx-induced-insulin resistance/dyslipidemia	-	+
Alteration of glucocorticoid clearance through hepatic CYP3A inhibition	-	+
Modulation of NR activity (PXR and LVR) by acting as ligands	-	+
Genetic/constitutional predisposition	+	+

+

: presence, -: absence, ?: unknown, * During stress and starvation, both fat and lean body mass are lost. Post stress and starvation body weight gain is primarily due to fat accumulation.

Table 4.

Differential Effects of Antiretroviral Drugs on Fat and Metabolism Associated with AIDS-Related Insulin Resistance and Lipodystrophy Syndrome (ARIRLS)*

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Class of drugs	Name of drug	Abbreviation	Lipo-atrophy	Lipo-hypertrophy	Dyslipidemia	Insulin resistance
PIs	Ritonavir	RTV	+/-	+	+++	++
	Indinavir	IDV	+/-	+	+	+++
	Nelfinavir	NFV	+/-	+	++	+
	Lopinavir	LPV	+/-	+	++	++
	Amprenavir Fosamprenavir	APV FPV	+/-	+	+	+/-
	Saquinavir	SQV	+/-	+	+/-	+/-
	Atazanavir	ATV	-	++	+/-	-
	Darunavir	DRV	-	+	+/-	+/-
NRTIs	Stavudine	D4T	+++	++	++	++
	Zidovudine	AZT, ZDV	++	+	+	++
	Didanosine	ddI	+/-	+/-	+	+
	Lamivudine	3TC	-	-	+	-
	Abacavir	ABC	-	-	+	-
	Tenofovir	TDF	-	-	-	-
	Emtricitabine	FTC	-	-	-	-
NNTRIs	Efavirenz	EFV	+/-	+/-	++, increased HDL	+
	Nevirapine	NVP	-	-	++, increased HDL	_
CCR5 inhibitor	Maraviroc	MVC	?	?	-	-
Integrase inhibitor	Raltegravir	RAL	?	?	-	-
Fusion inhibitor	Enfuvirtide	T20	?	?	-	-

Modified from (147) (Permission for re-use was obtained from Elsevier with the license number: 3012541054207)

*

These data should be considered with caution because discrepancies exist among studies that cannot be presented in one table.

Mechanistically, PIs act as inhibitors of the CYP3A4 enzyme, which metabolizes and inactivates glucocorticoids as we discussed above (11). Thus, these compounds may slightly increase circulating levels of endogenously produced cortisol by reducing its clearance in the liver, and participate in the development of ARIRLS. PIs also decrease hepatic lipase activity and modulate differentiation of pre-adipocytes (152-154). A possible underlying mechanism for this PI-mediated modulation of adipocyte activity is that these compounds change the expression levels of the peroxisome proliferation receptor (PPAR) γ and the CAAT/enhancer-binding protein (C/EBP) α (148). PPARγ is a NR family protein and acts as a pivotal regulator of glucose and lipid metabolism and development/differentiation of adipocytes (155). C/EBPα is a bZip family transcription factor, and plays also a key role in adipogenesis and adipocyte differentiation (156). In addition, PIs increase IL-6 and TNFα production by activating the NF-κB pathway in subcutaneous fat (157). These cytokines are known to play important roles in local inflammation and lipid accumulation in adipose tissue (158). The adverse effect of PIs may also result from induction of the endoplasmic reticulum stress or inhibition of the proteosomes (159,160).

NRTIs and NNRTIs

In addition to PIs, these classes of antiretroviral drugs are also associated strongly with development of ARIRLS. Among them, thymidine NRTI (tNRTI) stavudine and zidovudine cause severe lipoatrophy in AIDS patients, thus they were removed from the list of the first-line antiretroviral compounds in Western countries (161). These compounds demonstrate mitochondrial toxicity by inhibiting the mitochondrial DNA polymerase γ, facilitating generation of the reactive oxygen species in adipose tissues and possibly causing lipoatrophy in AIDS patients (147). Although weak, NNRTIs, such as efavirenz and nevirapine, also have an activity to develop lipodystrophy and dyslipidemia (147).

Modulation of NR Activity by Antiretroviral Drugs

In addition to above-indicated potential actions of antiretroviral drugs on the development of ARIRLS, some of these compounds can modulate the transcriptional activity of several NRs, such as the pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptors (LXRs) and the estrogen receptor α (ERα), and directly stimulate their transcriptional activity. Interestingly, these antiretroviral drugs were demonstrated to act potentially as ligands for the receptors in in silico structural analysis on the ligand-binding pocket of these receptors (154). PXR and CAR act as xenobiotic sensing receptors and induce drug metabolizing enzymes with broad ligand specificity for many chemical compounds, and several PIs can stimulate CYP3A4 and CYP2B6 promoter activity through activation of these receptors (154). Activation of PXR, either by its known ligands or transgenic expression of PXR, increases production of glucocorticoids in the adrenal glands by stimulating expression of the steroidogenic enzymes, such as CYP11A, CYP11B1, CYP11B2 and 3β-hydroxysteroid dehydrogenase, and develops Cushingoid manifestations in rodents (162), suggesting that PIs may increase cortisol production and participate in the development of ARIRLS indirectly through activation of PXR. Furthermore, PIs (ritonavir, atazanavir and darunavir) and maraviroc (CCR5 antagonist) activate the transcriptional activity of LXRα and/or LXRβ, while NNRTIs (tenofovir and efavirenz) stimulate ERα (but not ERβ) (154). Since LXRs are the receptors for regulating cholesterol/fatty acid metabolism and insulin actions, activation of these receptors by antiretroviral drugs may underlie pathophysiology of ARIRLS (163). In addition, LXRs and ERα cooperate with GR for expression of glucocorticoid-responsive genes, thus it is likely that these antiretroviral drugs enhance glucocorticoid actions indirectly through stimulating these NRs (164,165).

VIRAL FACTORS

Although antiretroviral drugs are generally accepted for causing ARIRLS, a small percentage of HIV-infected patients develop characteristic features of this syndrome prior to their introduction; HIV-infected patients who are not receiving antiretroviral therapy often have lipid abnormality, including elevated triglyceride levels, a high proportion of small and dense LDL particles, and low HDL cholesterol levels, similar to ARIRLS patients (166). Furthermore, different classes of chemical compounds that target different components of HIV/adipocyte biological pathways can develop similar ARIRLS manifestations in AIDS patients (147). These pieces of evidence thus suggest that the HIV infection itself could nonspecifically, -in part via inflammatory cytokine elevations and stress induced cortisol hypersecretion-, induce an insulin resistant phenotype (31). Pro-inflammatory cytokines, such as TNFα, IL-1 and IL-6, which are released from the HIV-infected macrophages localized in adipose tissues, do cause resistance to insulin and fat accumulation in neighboring adipocytes (158). In addition, these cytokines indirectly activate GR in adipose tissues by stimulating expression of the 11β-hydroxysteroid dehydrogenase-1 (11βHSD1), which converts inactive cortisone into active cortisol (167). Moreover, increased expression of GR is also reported in subcutaneous fat of zidovudine-treated AIDS patients (168). In this context, antiretroviral drugs might just exacerbate already present, smoldering insulin resistance and lipodystrophy, not expressed because of the known malnutrition of sick AIDS patients and the absence of sufficient calories to build visceral and other fat deposits (10,30,169). As manifestations of the sickness syndrome subside with treatment, the emaciated patient goes through refeeding with body weight gain of mostly fat, tilting the ratio of fat to lean body mass upward, further worsening insulin resistance.

HIV, in its 9.8 kb genomic information, encodes and produces 3 precursor proteins, the Gag, RNA polymerase and envelope polypeptides, whose processed products are the reverse transcriptase, protease, integrase, matrix, and capsid, as well as 6 accessory proteins, Tat, Rev, Nef, Vif, Vpr and Vpu (170) (Figure 3). Some of these polypeptides are virion-associated proteins incorporated in the viral particle and others are expressed in host cells where they direct viral replication and gene expression and several host cell functions. Since infection with HIV has a dramatic impact on host target cells, it is quite possible that some of these viral proteins modulate host cell glucose and lipid metabolism by changing the activity of GR in local tissues, such as in adipose tissue, skeletal muscles and liver, and participate in the development of ARIRLS. Indeed, there are several pieces of evidence indicating that AIDS patients have altered tissue sensitivity to glucocorticoids. First of all, they all develop reduction of innate and Th1-directed cellular immunity. Levels of plasma IL-2, IL-12 and IFN-γ, which direct cellular immunity, are suppressed in AIDS patients, while levels of IL-4 are increased (171,172). All changes can be induced by exogenously introduced glucocorticoids and are seen in hypercortisolemic patients with classic Cushing syndrome (173). AIDS patients also frequently present with muscle wasting and myopathy, as well as dyslipidemia and visceral obesity-related insulin resistance (174-176). Therefore, some unknown viral factor(s) might modulate tissue sensitivity to glucocorticoids in AIDS patients in a tissue-specific fashion, sparing their HPA axis preserving normal negative feedback sensitivity to glucocorticoids.

Figure 3.

Lineralized structure of the HIV genome and localization of vpr and tat coding region (shown in black boxes). HIV, in its 9.8 kb genomic information, encodes and produces 3 precursor proteins, the Gag (gag), RNA polymerase (pol) and envelope polypeptides (env), whose processed products are the reverse transcriptase, protease, integrase, matrix, and capsid, as well as 6 accessory proteins, Tat, Rev, Nef, Vif, Vpr and Vpu. LTR: long terminal repeat [modified from (170,177)]

In agreement with these reported findings, one of the HIV proteins, Vpr, which is a 96-amino acid virion-associated accessory protein with multiple functions, including influencing transcriptional activity and having a cell cycle-arresting effect, increases the action of GR by several fold, functioning as a potent GR coactivator (178). The GR coactivator activity of Vpr is biologically evident in the suppression of IL-12 production from monocytes and the expression of activated NF-κB ligand (RANKL) in lymphocytes (179,180). Similar to host p160 type coactivators, Vpr contains one LxxLL coactivator motif through which it binds to the ligand-activated and promoter-bound GR (178). GR-bound Vpr then attracts p300/CBP, and ultimately potentiates the transcriptional activity of GR by acting as a molecular adaptor between GR and p300/CBP (177,181) (Figure 4). p300/CBP are HAT coactivators also known as integrators or regulatory “platforms” for many signal transduction cascades by providing docking sites for many transcription factors, including NRs, CRE-binding protein (CREB), activator protein-1 (AP-1), NF-κB and the signal transducers and activators of transcription (STATs) (182) (Figure 4). Vpr easily penetrates the cell membrane to exert its biologic effects (183,184), thus its effects may be extended to tissues not infected with HIV.

Figure 4.

Linearized Vpr, Tat and p300 molecules and their mutual interaction domains. Vpr interacts with cellular molecules, such as NR, p300/CBP coactivators and 14-3-3, while Tat is physically associated with pTEFb elongation factor through its component Cyclin T1. Tat also binds p300/CBP and p160 type coactivators. Numerous transcription factors, transcriptional regulators and viral molecules bind the transcriptional coactivator p300. Binding sites of p160 NR coactivators and Vpr overlap with each other and they both bind NRs and p300/CBP. Thus, Vpr mimics the host p160 NR coactivators and enhances NR transcriptional activity. p300 facilitates attraction of transcription factors, cofactors and general transcription complexes by loosening the histone/DNA interaction through acetylation of histone tails by its histone acetyltransferase (HAT) domain. [modified from (29,30)]. CREB: CRE-binding protein, HAT: histone acetyltransferase, NF-κB: nuclear factor-κB, NR: nuclear hormone receptor, p/CAF: p300/CBP-associating factor, pTEFb: positive-acting transcription elongation factor b, Rb: retinoblastoma protein, SF-1: steroidogenic factor-1, STAT2: signal transducer and activator of transcription 2, TFIIB: transcription factor IIB.

Another HIV accessory protein, Tat, the most potent transactivator of the HIV long terminal repeat promoter, also moderately potentiates GR-induced transcriptional activity, possibly through accumulation of the positive-acting transcription elongation factor b (pTEFb) complex, that is comprised by the cyclin-dependent kinase 9 and its partner molecule cyclin T, on glucocorticoid responsive promoters (185) (Figure 4). Because Tat, like Vpr, also circulates in blood and exerts its actions as an auto/paracrine or endocrine factor by penetrating the cell membrane (186), it is possible that Tat modulates tissue sensitivity to glucocorticoids irrespectively of a cell’s infection by HIV. Concomitantly with Vpr, Tat may induce tissue hypersensitivity to glucocorticoids that might contribute to viral proliferation indirectly, by suppressing local immune system activity and by altering the host’s metabolic balance, with both functions being governed by glucocorticoids (30,46).

Vpr reduces tissue sensitivity to insulin not only through potentiating the actions of glucocorticoids, but also by modulating insulin’s transcriptional activity via interaction with the protein of the 14-3-3 family, which participates in the cell cycle arrest activity of Vpr (29,187). Insulin uses the forkhead transcription factors (FoxOs) to control gene induction; baseline unphosphorylated FoxOs are active, reside in the nucleus, and bind to their responsive sequences in the promoter region of insulin-responsive genes; in contrast, insulin activates Akt kinase, which phosphorylates specific serine and threonine residues of FoxOs rendering it inactive (188). Indeed, once FoxOs are phosphorylated at specific residues, they lose their transcriptional activity, by binding with 14-3-3 through phosphorylated residues and subsequently segregated into the cytoplasm (188). We found that Vpr moderately inhibited insulin-induced translocation of FoxO3a into the cytoplasm through inhibiting its association with 14-3-3 (187). Thus, Vpr may participate in the induction of insulin resistance by interfering with the insulin signaling through FoxOs/14-3-3 (29,151,177).

We further found that Vpr-mediated insulin resistance might be compounded by the ability of the viral protein to interfere with the signal transduction of PPARγ (183). Indeed, Vpr suppresses the c-Cbl associating protein (CAP) mRNA expression in pre-adipocyte cells and associated with the PPAR-binding site located in the promoter region of this gene. CAP is predominantly expressed in insulin-sensitive tissues and positively regulates insulin action, directly associating with both the insulin receptor and the c-Cbl proto-oncogene product (189). Vpr delivered either by exogenous expression or as a peptide added to media suppresses PPARγ agonist-induced adipocyte differentiation (183). Thus, circulating Vpr, or alternatively Vpr produced as a consequence of direct infection of adipocytes, may suppress differentiation of preadipocytes by acting as a corepressor of PPARγ-mediated gene transcription (29,183,190). We further found that Vpr regulates the transcriptional activity of PPARβ/δ as well, and alters cellular energy metabolism organized by mitochondria (191). Vpr disturbs the insulin signaling and induces hepatic steatosis by disrupting the transcriptional program of PPARs in the liver and adipose tissue in the animal models, such as the transgenic mice expressing Vpr specifically in these organ and tissue and the mice inoculated with the pump that continuously releases the synthetic Vpr peptide into circulation (192). Moreover, Vpr was demonstrated to induce fatty liver in mice via LXRα and PPARα dysregulation (193). Taken together, based on these pieces of evidence, Vpr may be a key factor for the development of lipodystrophy, insulin resistance and hyperlipidemia observed in HIV-infected patients through modulation of the GR/PPARs/LXR and FoxOs/14-3-3 activities.

HOST FACTORS

Several host factors may influence susceptibility and manifestation of ARIRLS. Variant alleles of APOC3, APOE contribute to an unfavorable lipid profile in patients with HIV infection, while application of antiretroviral therapy further worsens it (194). Another study identified that APOE polymorphism is also associated with the dyslipidemia seen in AIDS patients treated with PIs (195). One recent study demonstrated that polymorphisms of the genes involved in apoptosis and adipocyte metabolism are significantly related to the development of ARIRLS (196). Among the polymorphisms examined, ApoC3-455 variant is associated with lipoatrophy, while two variants of the adrenergic receptor β2 influence fat accumulation in ARIRLS patients (196). A polymorphism in the TNFα gene promoter is associated with development of lipodystrophy in one study, while this association was not confirmed in larger studies (194). Stavudine-induced lipoatrophy is associated with the HLA-B100*4001 allele among the genetic variants of HLA-A, HLA-B HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 (190). A newly identified polymorphism (Tth111I) in the GR gene is negatively associated with the development of some manifestations of ARIRLS in the African-American population (197). Finally, toxicity of antiretroviral drugs depends on their metabolism in each patient, which is partly determined genetically (196).

ACKNOWLEDGEMENTS

This literary work was supported by the intramural fund of the Sidra Medical and Research Center to T. Kino.

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