In the June 2, 2002 issue of the Journal of Virology, researchers report an astounding discovery: The protease inhibitor drugs Crixivan (indinavir) and Invarase (saquinavir) caused T cell death in healthy HIV negative donor blood in three separate experiments.

Authors Estaquier et al note: "We treated PBMC [peripheral blood cells‹cells circulating in the blood] from HIV-seronegative healthy donors with increasing concentrations of IDV [indinavir], SQV [saquinavir], or ddI for 3 days and monitored T-cell proliferation and cell death. Both IDV and SQV decreased T-cell proliferation mediated by CD3 MAb in three independent experiments performed with healthy donor cells with a mean decrease for SQV of 53% +/- 15% and a mean decrease for IDV of 48% +/- 12%."

In other words, three experiments showed Crixivan and Invarase decreased T-cell proliferation in the blood of healthy HIV-negative donors‹in the case of Invarase, by more than half.

The following Reuters article glosses over the damning data and puts a somewhat favorable spin on the findings with an equivocal summary statement that "protease inhibitors have the potential for both beneficial and detrimental effects on CD4+ T cells..." (The study abstract follows this news item)
(Courtesy Christine Maggiore, Founder/Director Alive & Well AIDS Alternatives)

Protease Inhibitors May Influence HIV-1 Associated CD4+ T-Cell Death NEW YORK (Reuters Health) Jul 02 - Studies of factors associated with peripheral blood T-cell apoptosis in HIV-1 infection indicate that antiretroviral agents may influence such processes independently of their antiretroviral effects. Dr. Jerome Estaquier of the Institut Pasteur in Paris, France and colleagues note that T-cell apoptosis plays an important part in the pathogenesis of HIV infection. To investigate, the researchers incubated CD4+ T cells from healthy donors in the presence of HIV-1. Even without T-cell stimulation, this induced C95 expression and primed the cells for CD95- or CD3-mediated cell death. Use of the reverse transcriptase inhibitor didanosine did not affect CD95-mediated CD4 T-cell death, showing that such apoptosis does not depend on CD4 T-cell infection. This suggests, say the investigators, that "HIV-1 triggers at least two distinct death pathways." One pathway, they indicate, involves CD95 and does not require viral replication, the other appears to be an independent viral-replication mediated pathway. In further studies, the team found that addition of the protease inhibitor saquinavir at a concentration of 0.2 M decreased HIV-mediated CD95 expression and thus cell death. However, addition of saquinavir or indinavir at concentrations of 10 M induced a loss of mitochondrial membrane potential and cell death. Thus, the investigators conclude, "protease inhibitors have the potential for both beneficial and detrimental effects on CD4+ T cells independent of their antiretroviral effects."

J Virol 2002 Jun;76(12):5966-73

Effects of antiretroviral drugs on human immunodeficiency virus type 1-induced CD4(+) T-cell death.

Estaquier J, Lelievre JD, Petit F, Brunner T, Moutouh-De Parseval L, Richman DD, Ameisen JC, Corbeil J.

EMI-U 9922 INSERM/Universite Paris 7, IFR02, AP-HP, Hopital Bichat-Claude Bernard, Paris, France. jestaqui@pasteur.fr

Apoptosis of peripheral blood T cells plays an important role in the pathogenesis of human immunodeficiency virus (HIV) infection. In this study, we found that HIV type 1 (HIV-1) primes CD4(+) T cells from healthy donors for apoptosis, which occurs after CD95 ligation or CD3-T-cell receptor (TCR) stimulation. CD95-mediated death did not depend on CD4 T-cell infection, since it occurred in the presence of the reverse transcriptase inhibitor didanosine (ddI). In contrast, apoptosis induced by productive infection (CD3-TCR stimulation) is prevented by both CD95 decoy receptor and ddI. Our data suggest that HIV-1 triggers at least two distinct death pathways: a CD95-dependent pathway that does not require viral replication and a viral replication-mediated cell death independent of the CD95 pathway. Further experiments indicated that saquinavir, a protease inhibitor, at a 0.2 microM concentration, decreased HIV-mediated CD95 expression and thus cell death, which is independent of its role in inhibiting viral replication. However, treatment of peripheral blood mononuclear cells from healthy donors with a higher concentration (10 microM) of an HIV protease inhibitor, saquinavir or indinavir, induced both a loss in mitochondrial membrane potential (DeltaPsim) and cell death. Thus, protease inhibitors have the potential for both beneficial and detrimental effects on CD4(+) T cells independent of their antiretroviral effects.

PMID: 12021329 [PubMed - indexed for MEDLINE]

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