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The Body Covers: The 6th Conference on Retroviruses and Opportunistic Infections
Poster Session 81: Mechanisms Responsible for Metabolic Complications of Antiretroviral Therapy

February 3, 1999

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

Abstract No. 665: Indinavir Enhances Retinoic Acid Signaling: Nelfinavir, Saquinavir, and Ritonavir Inhibit Retinoid Effects in vitro

Abstract No. 666: HIV Protease Inhibitors Block Adiogenesis and Increase Lipolysis in vitro


These two poster presentations are attempts to define the biochemical mechanisms affected by protease inhibitors that somehow are involved in lipid metabolism. At the Geneva AIDS Conference, a mechanism for the development of lipodystrophy proposed by Carr and colleagues claims that PIs interfere with the retinoic acid binding proteins in the cell cytoplasm. Ultimately, PI binding to this protein (CRABP-1) reduces the production of 9-cis retinoic acid which in turn results in a decrease of retinoid X receptor (RXR) activity. Since it is known that agents that selectively stimulate RXR activity result in improvement in dyslipidemia, it is suggested that PI therapy leads to the dyslipidemic effects associated with such therapy because of decreased RXR activity. However, a direct effect on retinoid-signaling has not been reported.


Abstract No. 665: Indinavir Enhances Retinoic Acid Signaling: Nelfinavir, Saquinavir, and Ritonavir Inhibit Retinoid Effects in vitro

Authored by J.M. Lenhard, J.E. Weiel, M.A. Paulik, J.M. Lehmann, G. Kozalka, and E.S. Furfine
Coverage by Jim Thommes, M.D.

Lenhard et al (abstract 665) set out to to test the effects of PIs on a retinoic acid responsive gene (alkaline phosphatase in C3H10T1/2 preadipocyte cells), and discovered that not all protease inhibitors behaved similarly in this enzyme system. Essentially, indinavir was shown to increase the activity of this retinoid-dependent enzyme, in contrast to the inhibitory effects of nelfinavir, saquinavir and ritonavir. Amprenavir, on the other hand, had no effect. Whether these in vitro effects translate to the clinical effects of dyslipidemia in real patients remain to be seen. The work, however, serves to demonstrate an alteration in retinoid signaling as proposed by Carr et al, and to suggest that not all protease inhibtors have the same signaling effect.


Abstract No. 666: HIV Protease Inhibitors Block Adiogenesis and Increase Lipolysis in vitro

Authored by J.M. Lenhard, J.E. Weiel, M.A. Paulik, L. Miller, O. Ittoop, S.G. Blanchard, and E.S. Furfine
Coverage by Jim Thommes, M.D.

In poster 666, Lenhard et al seek out the effects of protease inhibitors on adipocyte (the cells that store fat) metabolism and retinoid receptor signaling pathways (RXR and PPARgamma) in vitro. Alterations in adipocyte size and number may contribute to changes fat tissue mass and distribution (for example, lipodystrophy). Furthemore, after treatment with insulin, adipocyte size increases as a result of increased triglyceride synthesis in the cell (lipogenesis) and decresed lipid breakdown (lipolysis). Adipocyte numbers are influenced by agents that affect transition of stem cells into adipocytes (a process called adipogenesis), and this process is controlled by two nuclear receptors: PPARgamma, and RXRalpha. Agents like insulin, rexinoids and thiazolidiniones stimulate adipogenesis in vitro.

Their work demonstrated that saquinavir, nelfinavir and ritonavir prevented differentiation of stem cells into adipocytes, while inhibiting lipogenesis and stimulating lipolysis in existing adipocytes. Except for saquinavir, these effects were not due to binding of the PI to the PPAR or RXR receptors, but rather due to some other signaling effect via these receptors. Also, amprenavir and indinavir had little effect on adipogenesis in this model, suggesting that there is not a class-specific effect of PIs on fat metabolism in vitro.


Putting this scientific data into a clinical context is difficult at this point, although it is encouraging to see work that endeavours to understand the mechanisms underlying lipodystrophy in HIV disease. Lipid abnormalities (increased triglycerides and cholesterol, fatty infiltration of the liver, peripheral fat wasting) were noted in many patients prior to the availability of protease inhibitor therapy, telling us that lipid metabolism is already disturbed by the dynamics around HIV infection (probably through cytokines like IL-6 and TNFalpha). Although no one would argue that these dynamics are profoundly changed (and improved) by protease inhibitor therapy, protease inhibitors may well exert their own unique biochemical effects that, in a complementary fashion, amplifies the disturbed metabolic lipid dynamics that co-exist with HIV infection. Clearly, this area of inquiry continues to unfold.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!

See Also
More on HIV Medications
More Research on Protease Inhibitors



  
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Please note: Knowledge about HIV changes rapidly. Note the date of this summary's publication, and before treating patients or employing any therapies described in these materials, verify all information independently. If you are a patient, please consult a doctor or other medical professional before acting on any of the information presented in this summary. For a complete listing of our most recent conference coverage, click here.

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