Wednesday, July 15, 2009

Viremia-Independent T-Cell Protection by Another Protease Inhibitor

In opposition to the popular and even professional medical view that protease inhibitors protect T-cells by suppressing viremia, we previously noted the finding in a study that Ritonavir's protection of T-cells from cell death was independent of any viral suppression. In the case of protease inhibitor Indinavir, another study makes a similar observation and claims the following:

The findings indicate that IDV interferes with cell-cycle progression in primary cells but does not directly affect apoptosis. It is concluded that IDV may prolong cell survival indirectly by inhibiting their entry into cell cycle. In individuals on PI therapy, PI-mediated effects could potentially modulate immunologic responses independently of antiviral activity against HIV. (Blood. 2001;98:383-389)

The study's title, The HIV protease inhibitor Indinavir inhibits cell-cycle progression in vitro in lymphocytes of HIV-infected and uninfected individuals also points to the fact that such mechanisms of the drug would be the same for those who are seronegative.

2 comments:

NM said...

But these in vitro data don't seem to be reflected very strongly in clinical studies. The largest and most detailed study of immune reconstitution on ART found no correlation with the regimen used. And like all other studies of immune reconstitution I can think of, viral load suppression (VS in this quote) did correlate with CD4 T cell recovery:

"After initiation of ART, lower post-treatment VL, greater VL decline, and VS (VL ≤ 50 copies/mL) were associated with greater CD4 cell count gain in univariate regressions. In a multiple regression model that included age, sex, baseline CD4 cell count, baseline VL, and initial treatment assignment, VS was associated with greater CD4 cell count increase after adjustment for the other factors."

http://journals.lww.com/jaids/Fulltext/2006/08010/Effect_of_Baseline__and_Treatment_Related_Factors.6.aspx

Effect of Baseline- and Treatment-Related Factors on Immunologic Recovery After Initiation of Antiretroviral Therapy in HIV-1-Positive Subjects: Results From ACTG 384

Additional follow up from the study is in this paper:

http://www.journals.uchicago.edu/doi/full/10.1086/595888

Incomplete Reconstitution of T Cell Subsets on Combination Antiretroviral Therapy in the AIDS Clinical Trials Group Protocol 384

Cytotalker said...

NM, thank you for your observation. VL does appear to be correlated with improved CD4 counts, but these PI studies nevertheless suggest that the viral suppression, although correlated, may not be the causative factor where PIs are concerned, and that the CD4 and Viral Load markers may be the result of cell cycle control.

This is also consistent with immune activation preceding and correlating with virological failure. It is also similar to the effect of IL-2, which increases activation and VL initially and subsequently leads to long term lower proliferation due to naive CD4 cells and subsequent lower VL.

In all these cases, the studies point to the possibility of cell cycle control of the drugs and cytokines as independent variables, not forgetting that there exist other cytokine and hormonal influences which affect cell cycle and VL in the same manner. Many of these are documented in previous entries in this same blog.

Lastly, FWIW, the Ritonavir study's title does claim: "Human Immunodeficiency Virus Type 1 Protease Inhibitor Modulates Activation of Peripheral Blood CD4+ T Cells and Decreases Their Susceptibility to Apoptosis In Vitro and In Vivo"