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The HIV protease inhibitor darunavir prevents
kidney injury via HIV-independent mechanisms
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The DAD Study found reduced GFR associated with boosted Reyataz - is this due to creatinine increased, or kidney stones ????
https://www.natap.org/2015/CROI/croi_46.htm
There are several PIs approved for the treatment of HIV-1 and it is important to know whether our results are unique to DRV or are a "class effect" of PIs.
We believe that the effects of PI on the kidney may not unique to DRV. In addition to the published studies described above, we performed pilot studies with nelfinavir demonstrating similar effects as DRV upon cells in vitro and found in a small number of mice that daily intraperitoneal injection of nelfinavir for two weeks reduced renal expression of proinflammatory mediators in Tg26 kidneys (data not shown).
Coppo et al. reported that saquinavir reduced need for immunosuppression in HIV-negative patients with steroid-resistant or -dependent nephrotic syndrome14 and several PIs, most notably nelfinavir, have been shown to have HIV-independent effects on cellular pathways in the oncology literature44,45,46. We chose to use DRV in these studies for two reasons. First, neither saquinavir or nelfinavir are commonly used due to the improved side effect profiles and dosing options of newer PIs such as DRV, which is now the most commonly prescribed PI. Second, DRV is less likely to cause kidney injury due to intratubular crystallization, which has been most commonly reported with indinavir27,28, but also can occur with atazanavir (especially ritonavir-boosted regimens), or lopinavir29,30.
Since there has not been a major resurgence in the incidence of HIVAN with the recent shift to treating many HIV-positive persons with INSTI-based (PI free) regimens, it is likely that suppression of viremia with subsequent improvement in immune function is also critical for prevention of HIVAN. However, it is plausible that in persons with existing proteinuric kidney disease, DRV might provide additional benefit compared to PI-free regimens. Our data, combined with the previous small case series suggesting a beneficial effect of saquinavir in proteinuric kidney disease in HIV-negative patients14, provide rationale for future studies to determine if DRV-containing regimens confer more renoprotection compared to INSTI-based regimens in PLWH with proteinuric CKD.
Novel strategies are urgently needed to prevent and treat renal disease in PLWH and in HIV-negative persons. This study suggests that DRV may confer protection against the deleterious effects of HIV gene expression via mechanisms that are independent of effects on PR or viral replication. Future studies should determine the optimal ART regimens for HIV-positive patients with kidney disease and to determine the potential role of ART medications in non-HIV related kidney diseases.
The HIV protease inhibitor darunavir prevents kidney injury via HIV-independent mechanisms
Scientific Reports (2019)
Xiaobo Gao1, Alan Rosales 1, Heidi Karttunen1, Geetha M. Bommana2, Buadi tandoh1,
Zhengzi Yi3, Zainab Habib4, Vivette D'Agati5, Weijia Zhang3 & Michael J. Ross
Abstract
HIV-associated nephropathy (HIVAN) is a rapidly progressive kidney disease that is caused by HIV infection of renal epithelial cells with subsequent expression of viral genes, including vpr. Antiretroviral therapy ameliorates HIVAN without eradicating HIV from the kidneys and the mechanism by which it protects kidneys is poorly understood. Since HIV protease inhibitors have "off target" cellular effects, we studied whether darunavir, the most commonly prescribed protease inhibitor, protects kidneys from HIV-induced injury via mechanisms independent of HIV protease and viral replication. Renal epithelial cells were transduced with lentiviruses encoding HIV (lacking protease and reverse transcriptase), Vpr, or vector control. Darunavir attenuated HIV and Vpr-induced activation of Stat3, Src, Erk, and cytokines, which are critical for HIVAN pathogenesis. We then studied HIV-transgenic mice, which develop HIVAN in the absence of HIV protease or reverse transcriptase. Mice were treated with darunavir, zidovudine, darunavir + zidovudine, or control. Darunavir and darunavir + zidovudine reduced albuminuria and histologic kidney injury and normalized expression of dysregulated proteins. RNA-seq analyses demonstrated that darunavir suppressed HIV-induced upregulation of immune response genes in human kidney cells.
These data demonstrate that darunavir protects against HIV-induced renal injury via mechanisms that are independent of inhibition of HIV protease.
Results
Darunavir prevents dysregulation of key cellular pathways in human tubular cells in vitro
To test whether DRV can protect kidney cells from the deleterious effects of HIV via HIV protease-independent mechanisms, we studied the effects of DRV on renal tubular epithelial cells (RTEC). Conditionally immortalized human RTEC (HPT1b cells)33,34 were transduced with lentiviral vectors encoding either gag/pol-deleted HIV (based on the same provirus used in Tg26 HIVAN model, which lacks HIV protease), Vpr, or control lentivirus expressing EGFP and subsequently treated with DRV or vehicle control. Since activation of Stat3, Src, and Erk pathways are important in the pathogenesis of HIV-induced kidney injury19, we studied whether DRV could prevent their activation. HIV and Vpr-transduction of HPT1b cells increased phosphorylation of Stat3 (p < 0.01), Src (p < 0.01), and Erk (p < 0.01) compared to cells transduced with EGFP control lentivirus and DRV significantly prevented HIV and Vpr-induced phosphorylation of Stat3 (p < 0.01), Src (p < 0.01), and Erk (p < 0.01) (Fig. 1A,B). We also studied the effects of HIV and DRV upon activation of the mitogen activated protein kinases (MAPK) JNK and p38 in HPT1b cells. We did not detect an effect of HIV or Vpr transduction, or DRV treatment on JNK or p38 activation (Fig. 1A).
Since HIV-induced expression of proinflammatory mediators, including IL-6 and IL-8 are critical mediators of HIVAN pathogenesis35, we analyzed IL-6 and IL-8 expression in control, HIV- and Vpr-transfected HPT1b cells treated with or without DRV (Fig. 1C). HIV and Vpr transduction increased the expression of IL-6 (p < 0.01 and p = 0.03 respectively) and IL-8 (p < 0.01) in HPT1b cells compared to control-transduced cells. HIV and Vpr-induced upregulation of IL-6 and IL-8 was abrogated by DRV (Fig. 1C, p < 0.01). HIV also increased expression of IL-4 (p = 0.02) and IL-7 (p = 0.01) but expression was not affected by DRV. IL-4 and IL-7 expression were not changed after Vpr transduction with or without DRV (Fig. 1C).
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