The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function.
BACKGROUND
In HIV-infected patients some clinical and immunological benefits of antiretroviral therapy, which frequently include a combination of HIV protease inhibitors (PIs) and reverse transcriptase inhibitors (RTIs), cannot be solely explained by the drugs' action on viral enzymes. Proteasomes constitute the central protease of the ubiquitin ATP-dependent pathway involved in many cellular processes, as well as in HIV maturation and aggressiveness.


OBJECTIVE
To explore whether the PIs nelfinavir and saquinavir and the RTIs abacavir, nevirapine, delavirdine, stavudine and didanosine affect proteasome function in vitro and in vivo.


METHODS
Peptidase activity of purified human 26S and 20S proteasomes was assayed with and without the drugs at different concentrations. Intracellular proteasome proteolytic activity was evaluated by searching for ubiquitin-tagged proteins in HL60 cells incubated with and without the drugs.


RESULTS
At therapeutic dosages, nelfinavir and saquinavir inhibited proteasome peptidase activity and caused intracellular accumulation of polyubiquitinated proteins, a hallmark of proteasome proteolytic inhibition in vivo; the RTIs failed to evoke either effect.


CONCLUSIONS
Proteasomes are targeted by the two PIs but not the RTIs. Therefore, in HIV-infected patients the beneficial effect of a therapy including one of the two PIs should partly rely on inhibition of host proteasome function.
Piccinini
Marco
M
Department of Medicine and Experimental Oncology, University of Turin, Turin, Italy.
Rinaudo
Maria T
MT
Anselmino
Annalisa
A
Buccinnà
Barbara
B
Ramondetti
Cristina
C
Dematteis
Antonio
A
Ricotti
Emanuela
E
Palmisano
Lucia
L
Mostert
Michael
M
Tovo
Pier-Angelo
PA
D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D019888:Nelfinavir / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D019258:Saquinavir / Q000494:pharmacology*; D025801:Ubiquitin / Q000378:metabolism
D017320:HIV Protease Inhibitors; D011506:Proteins; D018894:Reverse Transcriptase Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D019888:Nelfinavir; D019258:Saquinavir