(Journal of Leukocyte Biology. 2006;80:1044-1051.)
© 2006
by Society for Leukocyte Biology
Human immunodeficiency virus infection and macrophage cholesterol metabolism
Michael Bukrinsky*,1 and
Dmitri Sviridov
* Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington, DC; and
Baker Heart Research Institute, Melbourne, Victoria, Australia
1 Correspondence: George Washington University, Department of Microbiology, Immunology and Tropical Medicine, 2300 I St., N.W., Ross Hall, Rm. 234, Washington, DC 20037. E-mail: mtmmib{at}gwumc.edu
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ABSTRACT
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Macrophages play a central role in the pathogenesis of atherosclerosis and are also a host for a number of viruses, most importantly, HIV. Many viruses, including HIV, require cholesterol for their replication and as a structural element. Cholesterol also plays a pivotal role in innate antiviral immune responses. Although impairing innate immune response by increasing cell cholesterol content may be a deliberate strategy used by a pathogen to improve its infectivity, enhancing the risk of atherosclerosis is likely a byproduct. Consistent association between HIV infection and elevated risk of atherosclerosis suggested a connection between virus-induced changes in cholesterol metabolism and atherogenesis, but the mechanisms of such connection have not been identified. We describe in this review various mechanisms enabling viruses to exploit macrophage pathways of cholesterol metabolism, thus diverting cholesterol for a purpose of increasing viral replication and/or for altering innate immune responses. To alter the cellular cholesterol content, viruses "hijack" the pathways responsible for maintaining intracellular cholesterol metabolism. The damage to these pathways by viral infection may result in the inability of macrophages to control cholesterol accumulation and may lead to formation of foam cells, a characteristic feature of atherosclerosis. Further elucidation of the mechanisms connecting viral infection and macrophage cholesterol metabolism may be fruitful for developing approaches to treatment of atherosclerosis and viral diseases.
Key Words: atherosclerosis • HIV-1 • Nef • reverse cholesterol transport • LXR
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INTRODUCTION
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Macrophages are the key players in innate and adaptive immune responses targeted at invading pathogens, including viruses, which when infecting macrophages, may interfere with their regulatory immune function, causing significant pathological problems. Below, we discuss recent findings describing how viruses and/or dysregulation of antiviral defense activity of macrophages may contribute to atherosclerosis, a disease not usually associated with viral infection. A key element of the pathogenesis of atherosclerosis, which is currently the most prevalent human disease, is impairment of cholesterol metabolism in macrophages [1
]. In this paper, we attempt to briefly review what little is known about why and how viruses affect normal macrophage cholesterol metabolism.
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MACROPHAGE CHOLESTEROL METABOLISM
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Macrophages, like all other cells except hepatocytes, are not capable of degrading cholesterol to any appreciable extent. Cell cholesterol content therefore is essentially a balance between cholesterol intake and cholesterol efflux. Two major mechanisms of cholesterol delivery to cells are receptor-mediated uptake of plasma low-density lipoprotein (LDL) and intracellular cholesterol biosynthesis. Each of these two major pathways of cholesterol delivery can fully satisfy the needs of a cell in case of cholesterol deficiency, and both are highly regulated [2
]. However, in some pathophysiological conditions, such as inflammation, high plasma LDL concentration and oxidative stress lead to the formation of modified, mostly oxidized, LDL [3
]. Modified LDL interacts with scavenger receptors (SRs) expressed on several cell types, including macrophages. The uptake of modified lipoproteins is not regulated in response to cell cholesterol content and may result in uncontrollable delivery of excessive cholesterol to macrophages [4
, 5
]. If not compensated by increased cholesterol efflux, this may lead to the accumulation of cholesterol and formation of lipid-laden foam cells, followed by development of a fatty streak in the arterial wall, one of the earliest steps in the progression of atherosclerotic plaque. SR family members SR-A and CD36 have been identified as receptors for modified lipoproteins on macrophages, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [6
, 7
].
Excess of cholesterol can be compensated by down-regulating cholesterol biosynthesis and expression of LDL receptors. However, the ability of cells to compensate for severe excess of cholesterol delivered by modified LDL by diminishing LDL uptake and cholesterol synthesis is limited. Two other mechanisms to compensate for excess of free cholesterol are synthesis of cholesteryl esters and cholesterol efflux. Although cholesteryl ester synthesis can provide temporary relief, continuous production of cholesteryl esters leads to excessive accumulation of intracellular lipid droplets. A combination of increased delivery of cholesterol to macrophages and insufficient cholesterol efflux would lead to accumulation of free and esterified cholesterol in the cells. Cholesterol-laden macrophages are a major constituent of the early atherosclerotic plaque and are a likely trigger for other elements of the pathogenesis of atherosclerosis, such as perpetuation of inflammation, phenotypical modification of smooth muscle cells, and overproduction of extracellular matrix proteins [1
]. Overloading of macrophages with free cholesterol leads to their apoptosis and necrosis, contributing to the necrotic and calcified core of the late atherosclerotic plaque [8
, 9
]. Hence, cholesterol homeostasis critically depends on the ability of cells to release excessive cholesterol by cholesterol efflux. Several major pathways of cholesterol efflux have been described.
An ATP-binding cassette transporter A1 (ABCA1)-dependent pathway consists of lipidation of apolipoprotein A-I (apoA-I) with cellular lipids and the formation of nascent high-density lipoprotein (HDL) particles [10
]. This is the main pathway of cholesterol efflux in many cell types, but it is most important in macrophages. Selective disruption of ABCA1 in macrophages leads to accumulation of cholesterol in these cells and development of atherosclerosis [11
, 12
]. Mutations in ABCA1 cause Tangier’s disease, a disorder characterized by the absence of HDL and nonexistent reverse cholesterol transport [13
]. ABCA1 knockout mice show no plasma HDL and accumulate cholesterol in macrophages [14
]. Conversely, ABCA1 transgenic mice show increased levels of HDL, increased reverse cholesterol transport, and improved protection against atherosclerosis [15
]. Expression of ABCA1 is transcriptionally regulated by the nuclear receptor liver X receptor (LXR), which acts as a heterodimer with the retinoid X receptor [16
]. Recently, two other ABC transporters, ABCG1 and ABCG4, were implicated in cholesterol efflux [17
18
19
]. These transporters mediate cholesterol efflux to the mature HDL but not to lipid-poor apoA-I.
The second pathway likely to play an important role in maintaining cholesterol balance in macrophages is the SR-B1-dependent pathway. SR-B1 was originally described as a HDL receptor, responsible for selective removal of cholesteryl esters from HDL in liver and steroidogenic tissues [20
], but later, its involvement in cholesterol efflux was also suggested [21
]. Transfection of cells with SR-B1 stimulates cholesterol efflux [21
], and its expression in macrophages is cardio-protective [22
].
Another pathway of cholesterol efflux especially relevant to macrophages is the caveolin-dependent pathway. Macrophages express caveolin-1 and caveolin-2 [23
]. Caveolin-1 is a critical component of caveolae and may also play a role in cholesterol trafficking; caveolin-2 is likely to play an accessory role [24
]. Most cholesterol released from cells to HDL likely originates from rafts and caveolae [25
], plasma membrane (PM) domains also intimately involved in cell signaling [26
] and virus replication [27
]. It follows that rafts and caveolae may be a point where cellular cholesterol efflux and virus replication pathways interconnect.
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CHOLESTEROL AND VIRAL REPLICATION
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A number of viruses depend on cholesterol for their replication. These include herpes simplex [28
], influenza [29
], murine leukemia virus [30
], vaccinia virus [31
], polyoma virus [32
], EBV [33
], Semliki Forest virus [34
], Ebola virus [35
], dengue virus [36
], measles virus [37
], and of course, HIV [38
, 39
]. Not all of these viruses infect macrophages, indicating that cholesterol requirement is not limited to infection of a particular cell type. Despite the wide acknowledgment that cholesterol is an important component of the membrane of enveloped (Env) viruses, surprisingly little is known about why and how cholesterol is involved in viral replication. Most of our knowledge about the role of cholesterol in viral replication is limited to the function of lipid rafts, the sphingolipid- and cholesterol-enriched microdomains of the PM. Several Env viruses use raft-like domains as platforms for virus assembly, e.g., HIV (see below), Ebola and Marburg viruses [40
], measles virus [41
], and influenza virus [42
, 43
]. Lipid rafts may also be used as entry points during viral infection, as suggested for influenza virus, based on the finding that hemagglutinin (the protein responsible for virus-cell fusion) concentrates in lipid rafts [44
]. A requirement of lipid rafts for virus entry has also been suggested for murine leukemia virus [30
], vaccinia virus [31
], dengue virus [36
], Ebola virus [35
], and EBV [33
].
Some viruses, such as SV-40 [45
], coxsackievirus [46
], and polyomavirus [47
], use caveolae as an entry point and exploit a caveolae-dependent endocytosis pathway to enter the cell (see ref. [48
] for review); most of these viruses, however, do not infect macrophages. Cholesterol plays an important role in this pathway, as illustrated by classical studies from the Helenius laboratory [45
], which demonstrated that non-Env virus SV-40 can infect cells using caveolin-dependent and caveolin-independent pathways for entry; however, both of these pathways are critically dependent on cholesterol.
Many recent studies have investigated the role of cholesterol in the life cycle of HIV. The role of intracellular cholesterol in HIV assembly was demonstrated by the finding that inhibition of cholesterol synthesis by lovastatin reduces HIV-1 particle production in infected cells [49
]. The molecular events underlying such dependency of HIV production on cholesterol have been scrutinized in several recent studies. HIV-1 budding from the host cell occurs at the lipid rafts, resulting in the high cholesterol:phospholipid molar ratio (>1.0) of the viral Env [27
, 50
]. This affinity for rafts is determined by the Pr55(Gag) precursor, which specifically associates with these membrane domains [51
52
53
]. Lipid raft-binding is mediated by the N terminus of Gag and is greatly enhanced by the Gag-Gag interaction domains. Depletion of cellular cholesterol and decrease in the number of rafts markedly and specifically reduce HIV-1 particle production [51
].
The effect of cholesterol depletion on HIV replication may also be indirect, resulting from multiple changes in cellular metabolism in response to changes in cellular cholesterol content and/or rate of cholesterol biosynthesis. For example, inhibition of cholesterol biosynthesis by statins reduces the steady concentration of all intermediates upstream of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, including those involved in protein prenylation. Reduction of prenylation of small G-proteins leads to inhibition of Rho-guanosinetriphosphatase (GTPase) and Rho-A activation, resulting in reduced virus entry [54
]. The latter is likely mediated by a known activity of Rho GTPases in controlling actin cytoskeleton rearrangements [55
]. Such a mechanism would be consistent with demonstrated activity of cortical actin as a protective barrier against HIV-1 infection [56
]. In addition, statins have pleiotropic beneficial effects independent from their effect on cholesterol biosynthesis, which may reduce HIV infection. These include anti-inflammatory properties resulting from the ability of statins to inhibit expression of the adhesion molecules [57
] or interaction of receptor-ligand pairs, such as ICAM-1 and LFA-1, on the endothelium and leukocytes [58
]. Inhibition of interaction of ICAM-1 with LFA-1 by statins diminishes HIV attachment to cells [59
].
In addition to the indirect effects of cholesterol-lowering drugs on HIV entry described above, several studies proposed a role for lipid rafts as entry points for HIV. This model relies on the known phenomenon of cocapping of CD4 and chemokine receptors at the sites of HIV entry [60
], which is also dependent on cholesterol [61
]. A study by Viard and colleagues [62
] demonstrated that cholesterol-depleted cells are unable to form clusters of CD4 and CXCR4 (or CCR5) necessary for virus-cell fusion. A similar observation was reported by Manes et al. [39
], who proposed a role for gp120-induced lateral reorganization of rafts to bring the CD4-gp120 complexes together with a raft-associated chemokine receptor. However, later reports demonstrated that association of CD4 and chemokine receptors with rafts is not necessary for HIV infection [63
, 64
]. The usual caveat of these findings is that many of them were done using cells overexpressing HIV receptors. Such cells often behave differently from primary cells, as demonstrated previously for signaling from chemokine receptors, which is essential for HIV entry into primary cells but is not necessary in transfected cells (ref. [60
] and references therein). What all these papers agree on is the dependence of HIV entry on cholesterol in the target cell membrane, as depletion of cholesterol inhibited HIV entry mediated by raft-associated and -excluded CD4 [63
].
The importance of cholesterol for infectivity of HIV virions was demonstrated by experiments, where treatment of HIV particles with cholesterol-sequestering drugs, such as ß-cyclodextrin, rendered the virus incompetent for cell entry [65
, 66
]. Cholesterol-depleted HIV-1 virions exhibit disruption of the virion lipid bilayer [65
] yet display normal levels of gp120 Env [66
]. Such virions bind to the cell surface CD4 receptor and coreceptor on target cells; however, they are not internalized upon binding [66
]. A study by Hildreth and colleagues [67
] demonstrated that ß-cyclodextrin permeabilizes the viral membrane, resulting in the loss of mature Gag proteins (capsid, matrix, and p6) without the loss of the Env glycoproteins. Electron microscopy revealed holes in the viral membrane of cholesterol-depleted virions and perturbations of the viral core structure [67
].
Taken together, these studies illustrate the critical role that cholesterol plays in the HIV life cycle.
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VIRUS-INDUCED CHANGES IN MACROPHAGE CHOLESTEROL METABOLISM
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Why?
Two suggestions were put forward as the reasons for viral requirement for cholesterol. First, Env viruses might need cholesterol as a structural component of their Env to facilitate fusion of the virus with the rafts, which contain a high number of virus receptors, and the role of cholesterol according to this hypothesis is purely structural: For optimal fusion, viral Env should have fluidity similar to that of the target membrane, and fluidity is determined by cholesterol and sphingolipid content. Hence, lipid composition of the viral Env is similar to that of rafts [68
]. Another likely reason for a number of Env viruses to use cholesterol-rich rafts for their entry is that rafts are also a hub of cellular signaling pathways [69
70
71
], including pathways related to innate immunity [72
]. Entering a cell through rafts/caveolae allows viruses to exploit a high concentration of cellular receptors required for virus entry in this area of PM, at the same time, excluding or disrupting cellular receptors involved in immune responses [72
]. Using rafts as an entry site makes it possible for HIV to synchronize entry with incapacitation of the target cell’s antigen presentation and also, induces signaling events necessary for subsequent spread of the progeny virus [73
, 74
]. Similar "hijacking" of rafts for the purpose of disrupting immune responses was described for Ebola virus [75
]. Evasion of antiviral innate immunity may be another reason behind elevation of cellular cholesterol levels characteristic for infection of macrophages by many viruses. Elevation of cholesterol levels in macrophages negatively affects various components of immune responses [76
], most likely, by down-regulating expression of the genes regulated by LXR, a nuclear receptor responding to cellular cholesterol content [77
].
High levels of cellular cholesterol are also beneficial for the late stages of viral replication. Some viruses, including HIV, use rafts not only for entry but also for budding. It was suggested that a reason for that is concentration of various molecules, viral and cellular, in one tight space, which is useful for the virus particle assembly [72
]. These molecules are transported to rafts and/or caveolae in association with cholesterol [26
], which is another reason for a virus to benefit from the high level of cellular cholesterol. Another suggestion was that budding from rafts allows for incorporation into the nascent virions of raft proteins, which would disrupt cellular immune responses in a target cell [72
]. Again, that would require a large number of cholesterol-rich domains on the PM and consequently, a supply of large amounts of cholesterol.
The above examples show that viruses depend on availability of cholesterol for their life cycle. Therefore, it appears to be a good strategy for the virus to take over parts of cellular cholesterol metabolism to ensure that there is sufficient supply of cholesterol and that cholesterol is located in the appropriate compartment—lipid rafts. Little is known about how viruses achieve this goal, and the following examples describe some interesting viral strategies. Much of the work was done on HIV virus, but the findings may have implications for other viruses as well.
How?
Zheng at al [78
] described one mechanism by which a virus, in this instance, HIV, may disrupt cellular cholesterol metabolism. The key element of HIV machinery involved in HIV-induced changes in cholesterol metabolism is an early-expressed HIV accessory protein, negative factor (Nef). First, Nef was shown to increase the cholesterol biosynthesis in transfected cells by up-regulating the expression of at least one of the enzymes (CYP51) in the cholesterol biosynthesis pathway (Fig. 1
, brown arrows). As this effect was shown in Chinese hamster ovary and Jurkat cells transfected with Nef, the presence of Nef alone was sufficient for the up-regulation. Consistent with this finding, van’t Wout et al. [79
] demonstrated that Nef up-regulates a number of other genes involved in cholesterol biosynthesis in T cells. Second, Nef, which is myristoylated and thus localizes to the PM, binds the newly synthesized cholesterol directly, using a conventional cholesterol recognition motif in the carboxyl terminal region of the protein, and then transports it to the rafts [78
] (Fig. 1
, brown arrows).
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Figure 1. Proposed mechanisms of viral interference with macrophage cholesterol metabolism. Infection of macrophage by HIV results in expression of Nef, which is capable of binding cholesterol and enhancing cholesterol trafficking to rafts, sites of HIV budding. As a result, cholesterol content of rafts elevates, and cholesterol content of endoplasmic reticulum (ER) decreases. The latter is compensated by the elevation of cholesterol biosynthesis (brown arrows). Nef also redistributes ABCA1, causing a sharp inhibition of cholesterol efflux (yellow arrow). Nonspecific reaction of macrophage to infection includes activation of TLRs, which inhibit expression of genes controlled by LXR. One of these genes is ABCA1, and that may inhibit cholesterol efflux (green arrow) further. The combined effect of all three pathways is an increase in cellular cholesterol content and shifting of intracellular cholesterol trafficking from ABCA1 and efflux to rafts for virus assembly.
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When mechanisms of these effects of Nef were analyzed, it was found that mutations in Nef affecting its trafficking to the PM as well as those affecting its ability to bind cholesterol eliminated its effect on cholesterol biosynthesis and trafficking. A model proposed by Zheng el al. [78
] suggests that Nef binds cholesterol in the ER and transports it to rafts for incorporation into the virus. It must be mentioned, however, that a recent study by Sol-Foulon et al. [80
] argues against the role of Nef in raft segregation of viral-structural proteins, thus weakening the case for the role of Nef-associated cholesterol in virion assembly. Nevertheless, as a result of depletion of an intracellular cholesterol pool by Nef, cholesterol biosynthesis would be up-regulated. At the same time, the cholesterol content and probably the number of rafts would increase, thus increasing HIV budding from the rafts. The molecular mechanisms of this phenomenon are not known, and it is unclear what cellular proteins (e.g., elements of intracellular cholesterol trafficking machinery), if any, are required for Nef-specific cholesterol trafficking. It is not known whether Nef can execute the observed effects on its own or binds a cellular counterpart and subverts an existing cholesterol trafficking pathway to do the job. The latter would be consistent with the common strategy often used by viruses: not to introduce a new pathway but rather, exploit an existing cellular pathway for their purposes. Tweaking with a regulatory pool of intracellular cholesterol, however, would almost inevitably result in other changes in cholesterol homeostasis, such as up-regulation of LDL receptors and HMG-CoA reductase, further increasing cell cholesterol content. An increase in macrophage cholesterol content would almost certainly lead to an increased risk of the development of atherosclerosis.
Castrillo et al. [81
] recently described another mechanism of how a virus can interfere with cellular cholesterol metabolism. The proposed mechanism is not specific for a particular virus but rather represents a nonspecific response to a bacterial or a viral pathogen. The key element of this pathway was inhibition of the expression of LXR-dependent genes. Expression of LXR itself was not altered, suggesting involvement of LXR-related signaling downstream from LXR. Indeed, it was shown that activation of TLRs, more specifically, TLR3 and TLR4, interferes with a LXR-inducible signaling pathway and consequently, inhibits LXR-dependent gene expression (Fig. 1
, green arrow). The molecular mechanism of this effect seems to be a competition between LXR and a transcription factor IFN-regulator factor 3 for a common coactivator, p300/CREB-binding protein. One of the genes activated by LXR is ABCA1, a key element of cholesterol efflux pathway (see above). Consequently, cholesterol efflux from macrophages was inhibited when TLR was activated. Inhibition of cholesterol efflux, similar to enhancing the cholesterol delivery to cells, would lead to increased cell cholesterol content. In the case of TLR, however, it is not clear if this is a deliberate strategy of a pathogen or an adverse effect of the activation of cellular immune responses. The end result of TLR3/4 signaling pathway is production of antiviral response factors, such as IFN-ß; therefore, deliberate activation of TLRs might not be in the best interest of a pathogen but rather, a defensive response of the macrophage. Conversely, LXR-dependent gene expression is also involved in innate immune responses [77
]. One way or another, accumulation of cholesterol in macrophages would have a profound effect on the risk of development of atherosclerosis.
A variation on the same theme of cholesterol efflux alteration by an invading pathogen leading to a virus-dependent increase of cellular cholesterol content was identified recently by the authors of this paper and others in HIV-infected macrophages (Zahedi Mujawar, Honor Rose, Matthew P. Morrow, Tatiana Pushkarsky, Larisa Dubrovsky, Nigora Mukhamedova, Anthony Dart, Ying Fu, Jan M. Orenstein, Yuri V. Bobryshev, M.B., and D.S., submitted manuscript). We found that infection of macrophages with HIV leads to a dramatic inhibition of cholesterol efflux from these cells (Fig. 1
, yellow arrow). The effect was specific for HIV, and the key viral element of this phenomenon was found to be Nef. Nef-deficient HIV was not active in inhibiting cholesterol efflux, and transfection of murine macrophages with Nef was sufficient to cause inhibition of cholesterol efflux. The key cellular element of this phenomenon was found to be ABCA1: Nef caused redistribution of ABCA1 to the cell surface and inhibited trafficking of ABCA1 between PM and ER, previously shown to be required for ABCA1-mediated cholesterol efflux [82
, 83
]. Relocalization of ABCA1 to the PM also inhibited internalization of apoA-I, a major acceptor of cholesterol from macrophages. As a result, HIV-infected (but not 
Nef-HIV-infected) or Nef-transfected macrophages rapidly accumulated substantial quantities of cholesteryl esters and morphologically resembled foam cells. If this phenomenon occurs in vivo, this almost inevitably would lead to the increased risk of the development of atherosclerosis in HIV-infected patients.
The following chain of events can be hypothesized combining all three mechanisms (Fig. 1)
. HIV infection leads to the expression of Nef, causing increased cholesterol biosynthesis and trafficking of cholesterol to the PM and rafts for virus assembly. At the same time, cholesterol efflux from macrophages is reduced by a Nef-mediated decrease of ABCA1 abundance and impairing of its trafficking. As a result, the intracellular flow of cholesterol would be diverted from the regulatory pools in the ER and from the efflux pathway to the raft regions of the PM. Overloading of the PM with free cholesterol in the absence of active cholesterol efflux would most likely lead to a compensatory internalization of excessive cholesterol into intracellular compartments [84
], enhanced synthesis of cholesteryl esters, and formation of cholesterol-laden macrophages, the initial step in pathogenesis of atherosclerosis.
Consequences: HIV and atherosclerosis
HIV infection is consistently associated with increased risk of development of atherosclerosis [85
, 86
] and at least a threefold increased risk of coronary artery disease (CAD) [87
, 88
]. This association was previously attributed exclusively to the adverse effects of antiretroviral therapy. In HIV-infected patients, persistent hypoalphalipoproteinemia and hypertriglyceridemia associated with elevated levels of total and LDL cholesterol result in a highly atherogenic lipoprotein profile [89
], which contributes to the increased risk of development of atherosclerosis. Although many changes in cholesterol metabolism, such as elevation of LDL [90
] and increased cholesterol uptake through induction of CD36 expression [91
], are likely to be caused by antiretroviral therapy [92
], the relative contributions of therapy and the HIV infection itself to cholesterol metabolism remain to be determined. Preliminary studies from our [93
] and other [86
, 90
, 94
] laboratories indicate that HIV infection itself might play a key role in increasing risk of CAD. HIV infects macrophages and as described above, impairs reverse cholesterol transport in these cells. Impairment of cholesterol efflux from macrophages leads to accumulation of intracellular cholesterol [95
] and development of atherosclerosis in animal models [12
] and in humans [13
]. This process is especially rapid when associated with dyslipidemia. It is, therefore, reasonable to suggest that infection of macrophages with HIV, when associated with dyslipidemia, caused by antiretroviral therapy, may cause accumulation of cholesterol in macrophages and rapid development of atherosclerosis.
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CONCLUSIONS
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Summarizing the recent findings, it would be reasonable to suggest that viral infection would often lead to an elevation of cholesterol content in target cells. This statement awaits confirmation in experiments with primary macrophages, as most of the studies so far were performed using cell lines. The exact mechanisms responsible for this effect remain to be elucidated. It is likely that these mechanisms will be different for different viruses, so these studies would benefit from collaborative efforts of virologists and cholesterol metabolism experts. Studies along these lines are expected to reveal new interactions between viral proteins and components of the cellular cholesterol metabolism machinery and may provide new insights into viral biology and regulation of cellular cholesterol. Another reason for virus-induced accumulation of intracellular cholesterol may be a nonspecific, TLR-mediated response to viral infection. Viral components inducing such response need to be defined. Whatever the mechanism, the end result would almost certainly be an accumulation of excessive cholesterol. If infection persists over a long period of time, that by itself may be sufficient to cause a substantial rise in the risk of atherosclerosis. In acute infections, cholesterol-loaded macrophages may contribute to initiation of atherosclerotic plaque formation, which then may proceed even in the absence of newly infected cells. Testing of this model awaits large-scale clinical studies with chronically infected patients, and HIV infection appears to present the best opportunity for such studies. A connection between infection and atherosclerosis has long been suspected, as some viruses (such as Herpes virus or cytomegalovirus) were found in atherosclerotic plaques and were epidemiologically associated with an elevated risk of development of atherosclerosis [96
97
98
]. Now, this suspicion is slowly gaining a biochemical and molecular basis.
Received February 23, 2006;
revised April 10, 2006;
accepted April 17, 2006.
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