COMPLICATIONS ASSOCIATED WITH THE USE OF HIV PROTEASE INHIBITORS
There has been intense research interest in the adverse effects of HIV protease inhibitors and the influences of these drugs on cellular biology that may be related to their therapeutic effects (e.g., inhibition of the proapoptotic activities of HIV protease) and that may also be independent of their antiretroviral properties (e.g., mitochondrial membrane-stabilizing effects of nelfinavir,72 inhibition of caspase-dependent apoptosis associated with ritonavir73,74).
As reviewed in Chapter 25 and elsewhere,75 HIV protease inhibitors, therefore, exhibit pleiotropic activities that generally promote antiapoptotic rather than proapoptotic activities in nonmalignant cell populations, a view that is supported by the fact that complications of these drugs do not involve tissue destruction (in contrast to the effects of NRTI drugs on adipose tissue, for example) but, rather, represent alterations in whole-body metabolism. The most notable complications associated with drugs from the HIV protease inhibitor group include dyslipidemia and insulin resistance, as reviewed elsewhere.76 However, the following examples are provided that may illustrate specific associations between HIV protease inhbitors and the modulation of apoptosis. It is an interesting conundrum that in these cases, the same cellular mechanisms that provide protection from apoptotic cell death may also be implicated in the pathogenesis of adverse events.Diarrhea Associated with Nelfinavir: A Common Pathway
with Antiapoptotic Properties?
Although elucidating the pathogenesis of diarrhea associated with the HIV protease inhibitor nelfinavir has not generated the same level of enthusiasm within the research community as other topics, this issue is, nevertheless, of considerable clinical importance and has produced a seminal paper.
Approximately 40 to 50% of patients treated with nelfinavir develop chronic diarrhea, which requires drug treatment in one third of cases and also is a relatively frequent reason for drug discontinuation.77 This effect is specific to nelfinavir within the HIV protease inhibitor drug class, although less severe diarrhea also was observed with lopinavir therapy.77 In their impressive study on this subject, Paul Rufo, Patricia Lin, and their colleagues at Harvard University and Johns Hopkins University characterized this as a secretory form of diarrhea (i.e., involving excessive intestinal fluid secretion) among eight patients admitted for investigation and also went on to demonstrate that the underlying cellular defect involves altered cellular calcium metabolism in studies using intestinal (T84) cell lines.78 This mechanism involves the potentiation of muscarinic signaling that triggers increased chloride conductance (and thus water and sodium secretion into the intestinal lumen), so that this physiological response is not appropriately downregulated. At a more fundamental level, this defect may be described as a prolongation of cellular calcium entry in response to the release of intracellular calcium stores (“store-operated” calcium entry).78This topic will be addressed further, after examining another effect of nelfinavir treatment that is also of biological and clinical significance and one that is directly interested in the regulation of apoptosis by this drug. In this study, Andrew Badley and his colleagues from the University of Ottawa demonstrated that nelfinavir stabilized the mitochondrial membrane potential in T lymphocyte cell lines (Jurkat and H9), inhibiting apoptotic signaling by preventing the opening of the permeability transition pore and the subsequent release of mitochondrial apoptotic mediators such as cytochrome c and apoptosis-inducing factor (AIF)79 (see also Chapter 25). These data, therefore, describe an important antiapoptotic function of nelfinavir that is clinically relevant,80 that is independent of antiretroviral activity, and that targets immune cells intrinsically involved in HIV-1 infection.
Can these disparate nelfinavir effects—one potentially therapeutic, the other clinically problematic—be attributed to a common mechanism? Any answer is speculative, but it is notable that mitochondria play an important role in buffering intracellular calcium flux and, therefore, contribute to the regulation of store-operated calcium uptake in response to hormonal signals mediated via phosphoinositide pathways (e.g., muscarinic acetylcholine activation).81,82 Hence, the ability of nelfinavir to maintain the mitochondrial transmembrane potential in a more energized state may also prolong store-operated calcium signaling and inhibit its physiological downregulation.83 The obvious therapeutic benefits associated with antiapoptotic HIV drugs may, therefore, require consideration of potential adverse effects associated with reduced flexibility of intracellular calcium signaling, although it must be stressed again that such associations are entirely unproven at this point.
Ritonavir, Proteasomal Inhibition, and Metabolic Complications
A second example in which an intrinsic effect of HIV protease inhibitor therapy may contribute to multiple outcomes involves ritonavir. This drug selectively inhibits the chymotrypsin-like activity of the 20S proteasome at therapeutic concentrations (although enhancing its tryptic activity), thus potentially affecting antigen presentation and cytotoxic T lymphocyte responses.84,85 This attribute may also contribute to the antiapoptotic properties of ritonavir, in keeping with complex effects of proteasome inhibitors on apoptosis,86 although there is more substantial evidence that this drug inhibits the activation of selected caspases.73,74,87
Proteasomal inhibition caused by ritonavir is likely to provide an explanation for the specific effect of this drug to cause elevated triglyceride levels after short-term drug exposure, even in HIV- uninfected individuals.88 This seems to reflect increased hepatic triglyceride synthesis and secretion, which, in turn, is related to reduced proteasomal degradation of a key transcriptional factor (sterol regulatory binding protein [SREBP-1]) involved in regulating lipid metabolism in response to insulin and fatty acid stimuli.89-93 This means that hepatic triglyceride production is constitutively activated due to the nuclear retention of SREBP-1.90-92 It is uncertain at present whether the propensity of ritonavir therapy to cause hypertriglyceridemia is associated with increased risk of cardiovascular disease, but this example highlights how tissue-specific effects of HIV protease inhibitor may have diverse consequences mediated by a single mechanism.
conclusions
One of the messages that is becoming increasingly clear from the large body of research devoted to antiretroviral drug toxicity is that each drug has a unique toxicity profile, implying that although considering drug “class effects” can be useful to some extent (guiding research into NRTI-associated mitochondrial toxicity, for example), important differences remain between individual drugs. These may be apparent in terms of overall risk of toxicity, tissue specificity (bearing in mind that one mechanism can give rise to disparate outcomes in different tissues), and phenotypic expression. With regard to the role of apoptosis in these toxicity syndromes, it is fair to say that there are limited data that directly relate apoptosis to clinical or pathological outcomes, compared with the larger body of evidence relating to the involvement of apoptosis in HIV disease pathogenesis and progression reviewed elsewhere in this book. Nevertheless, the mechanisms underlying these drug toxicities are becoming better defined, revealing complex and intriguing insights into the regulation of whole-body metabolism as well as cellular integrity and function.
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