HIV protease inhibitors modulate apoptosis signaling in vitro and in vivo

Abstract

HIV protease inhibitors are an integral part of effective anti-HIV therapy. The drugs block HIV protease, prevent proper packaging of HIV virions, and decrease the HIV viral burden in the peripheral blood of infected individuals. In addition to direct anti-viral effects, the HIV protease inhibitors also modulate apoptosis. A growing body of work demonstrates the anti-apoptotic effects of HIV protease inhibitors on CD4+ and CD8 + T cells during HIV infection. The mechanism of this apoptosis inhibition is supported by several proposed hypotheses for how they alter the fate of the cell, including preventing adenine nucleotide translocator pore function, which consequently prevents loss of mitochondrial transmembrane potential. More recently, the anti-apoptotic effects of the HIV protease inhibitors have been tested in non-HIV, non-immune cell, whereby protease inhibitors prevent apoptosis, and disease in animal models of sepsis, hepatitis, pancreatitis and stroke. Interestingly, when HIV protease inhibitors are used at supra-therapeutic concentrations, they exert pro-apoptotic effects. This has been demonstrated in a number of tumor models. Although it is unclear how HIV protease inhibitors can induce apoptosis at increased concentrations, future research will define the targets of the immunomodulation and reveal the full clinical potential of this intriguing class of drugs.

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

“…Much emphasis has been recently placed on unconventional (i.e., non-directly virus-mediated) mechanisms of CD4 ϩ T cell depletion during HIV infection of humans and SIV infection of macaques (48). Among these mechanisms, the apoptosis of bystander, uninfected CD4 ϩ T cells may be prominent (49,50). One intriguing possibility raised by our study is that the observed disconnection between control of viral load and disease progression is caused by the presence of different mechanisms of CD4 ϩ T cell depletion in vaccinated vs unvaccinated animals.…”

“…One year after priming with the MVA-based vaccine, both experimental groups and an additional control group of five unvaccinated animals were challenged with SIVmac239 (10,000 fifty percent tissue culture-infective doses (TCID 50 ) prepared from COS-1 cell supernatant after transfection with DNA from a pBR239 full-length SIVmac239 clone) provided by the laboratory of Louis Picker (Oregon Health Sciences University and Oregon National Primate Research Center, Beaverton, OR).…”

In-vitro effects of protease inhibitors on BAX, BCL-2 and apoptosis in two human breast cell lines (with corrigendum)

“…It has been shown previously that protease inhibitors have potent antiapoptotic effects in different cellular systems, the majority of which are immune cells. 19,20,32,39 These studies reported that the protease inhibitors investigated inhibited drug induced apoptosis. This anti-apoptotic property, (exhibited by protease inhibitors at concentrations similar to those levels achieved in people receiving the drugs) is an important http://www.sajs.co.za…”

“…Numerous studies 19,20,32,39 have shown that protease inhibitors have potent anti-apoptotic effects in a variety of cell systems, the majority of which are immune cells. We assessed the anti-apoptotic effects of LPV/r to test whether these generalised effects are seen in the currently investigated human breast cell lines and to test whether they alter apoptosis via a pathway other than the BAX/BCL-2 pathway, since they had no significant effects on BAX and BCL-2 mRNA expression (Figure 2).…”

Short Communication: Enhanced CD8+ T Cell Apoptosis in HIV-Infected Adolescents with Virologic Failure on Protease Inhibitor-Based Therapy

“…This finding was surprising, given the beneficial effects of PI on CD4 + T cell retention and reconstitution previously reported in some HIV + patients. [2][3][4] However, PI may exert differential cellular effects on different cell types, including proapoptotic effects in some cell types. 4 Moreover, there were earlier reports of unfavorable clinical outcomes in PI + ART compared to PI À ART.…”