An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses

André, Patrice; Groettrup, Marcus; Klenerman, Paul; Giuli, Rita de; Booth, Bruce L.; Cerundolo, Vincenzo; Bonneville, Marc; Jotereau, Francine; Zinkernagel, R M; Lotteau, Vincent

doi:10.1073/pnas.95.22.13120

Cited by 258 publications

(195 citation statements)

References 32 publications

Supporting

Mentioning

180

Contrasting

Order By: Relevance

“…This immunomodulatory effect was neither due to the inhibition of viral replication nor to a direct effect on CTL activation, but was attributed to a reduction in the presentation of immunodominant LCMV epitopes. Interestingly, Ritonavir was found to inhibit the chymotrypsin-like activity of the 20S proteasome in vitro, while the trypsin-like activity was enhanced (41,42). We reasoned that the modulation of proteasome activity would account for the in vivo reduction of Ag presentation, but we could not exclude that this effect was, at least in part, due to the inhibition of other proteases in APC.…”

Section: Discussionmentioning

confidence: 94%

“…Recently, we have found that the treatment of LCMV-infected mice with the HIV-1 protease inhibitor Ritonavir at therapeutic concentrations markedly inhibited the generation and expansion of LCMV-specific CTLs in vivo (42). This immunomodulatory effect was neither due to the inhibition of viral replication nor to a direct effect on CTL activation, but was attributed to a reduction in the presentation of immunodominant LCMV epitopes.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Schwarz

Giuli

Schmidtke

et al. 2000

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The complete inhibition of proteasome activities interferes with the production of most MHC class I peptide ligands as well as with cellular proliferation and survival. In this study we have investigated how partial and selective inhibition of the chymotrypsin-like activity of the proteasome by the proteasome inhibitors lactacystin or epoxomicin would affect Ag presentation. At 0.5–1 μM lactacystin, the presentation of the lymphocytic choriomeningitis virus-derived epitopes NP118 and GP33 and the mouse CMV epitope pp89–168 were reduced and were further diminished in a dose-dependent manner with increasing concentrations. Presentation of the lymphocytic choriomeningitis virus-derived epitope GP276, in contrast, was markedly enhanced at low, but abrogated at higher, concentrations of either lactacystin or epoxomicin. The inhibitor-mediated effects were thus epitope specific and did not correlate with the degradation rates of the involved viral proteins. Although neither apoptosis induction nor interference with cellular proliferation was observed at 0.5–1 μM lactacystin in vivo, this concentration was sufficient to alter the fragmentation of polypeptides by the 20S proteasome in vitro. Our results indicate that partial and selective inhibition of proteasome activity in vivo is a valid approach to modulate Ag presentation, with potential applications for the treatment of autoimmune diseases and the prevention of transplant rejection.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Schwarz

Giuli

Schmidtke

et al. 2000

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In support of this concept, the direct inhibitory effects of the protease inhibitor ritonavir on CTL function and on antigen presentation, demonstrate that this class of agents directly modulates immune function. 103 Furthermore, several lines of evidence suggest that protease inhibitors may affect T cell turnover in a manner that is independent of changes in viral load. If rebound in CD4 T cell counts are solely related to decreases in viral load, one would predict similar increases in CD4 T cell levels with similar degrees of viral suppression whether this was achieved by protease inhibitor or non-protease inhibitor based therapy.…”

Section: Discussionmentioning

confidence: 99%

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

et al. 1999

View full text Add to dashboard Cite

T cells from HIV infected patients undergo spontaneous apoptosis at a faster rate than those from uninfected patients, are abnormally susceptible to activation induced cell death (AICD), and undergo increased apoptosis in response to Fas receptor ligation. These observations have led to the hypothesis CD4 T cell apoptosis may be a mechanism of CD4 T cell depletion and the pathogenesis of AIDS. Successful treatment of HIV infected patients is accompanied by quantitative and qualitative improvements in immune function reflecting at least partial reversibility of the underlying pathogenesis of HIV. In this report we correlate improvements in markers of immune function with a decrease in apoptosis, and changes in its regulation. Therapy with nelfinavir plus saquinavir in combination with two nucleoside analogue inhibitors of reverse transcriptase dramatically reduces plasma viremia and increases CD4 T cell counts. Coincident with these improvements, CD38 and HLA-DR coexpression on both CD4 and CD8 T cells decrease, and CD45RA and CD62L coexpression increase. Furthermore, spontaneous apoptosis decreases in both CD4 and CD8 T cells (CD4 apoptosis 17.4 vs 2.6%, P=0.005; CD8 apoptosis 15.0 vs 1.0%, P50.001), as does both Fas mediated apoptosis (CD4 apoptosis 19.0 vs 3.5%, P=0.03; CD8 apoptosis 13.7 vs 1.5%, P=0.002) and CD3 induced AICD (CD4 apoptosis 13.7 vs 3.2%, P=0.001; CD8 apoptosis 29 vs 2.2%, P=0.08). Changes in apoptosis are not associated with changes in Fas receptor expression, but are significantly correlated with changes in activation marker profiles. Although this suggests a possible regulatory role for the apoptosis inhibitory protein FLIP, direct assessment did not reveal quantitative differences in FLIP expression between apoptosis resistant PBL's from HIV negative patients, and apoptosis sensitive PBL's from HIV positive patients. These findings support the hypothesis that apoptosis mediates HIV induced CD4 T cell depletion, but indicate the need for further studies into the molecular regulation of HIV induced apoptosis.

show abstract

“…During chronic infections or cancer, it may be beneficial to alter the spectrum or level of epitopes produced in vivo to boost T cell recognition or to increase the potential targets for T cell recognition. The HIV protease inhibitor ritonavir has been reported to impair proteasome activity (59). It may be interesting to determine whether this compound or other proteasome inhibitors that can be used in vivo alter CTL activity toward epitopes such as NP [147][148][149][150][151][152][153][154][155] in animal models.…”

Section: Discussionmentioning

confidence: 99%

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Wherry

Golovina

Morrison

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

The proteasome is primarily responsible for the generation of MHC class I-restricted CTL epitopes. However, some epitopes, such as NP147–155 of the influenza nucleoprotein (NP), are presented efficiently in the presence of proteasome inhibitors. The pathways used to generate such apparently “proteasome-independent” epitopes remain poorly defined. We have examined the generation of NP147–155 and a second proteasome-dependent NP epitope, NP50–57, using cells adapted to growth in the presence of proteasome inhibitors and also through protease overexpression. We observed that: 1) Ag processing and presentation proceeds in proteasome-inhibitor adapted cells but may become more dependent, at least in part, on nonproteasomal protease(s), 2) tripeptidyl peptidase II does not substitute for the proteasome in the generation of NP147–155, 3) overexpression of leucine aminopeptidase, thymet oligopeptidase, puromycin-sensitive aminopeptidase, and bleomycin hydrolase, has little impact on the processing and presentation of NP50–57 or NP147–155, and 4) proteasome-inhibitor treatment altered the specificity of substrate cleavage by the proteasome using cell-free digests favoring NP147–155 epitope preservation. Based on these results, we propose a central role for the proteasome in epitope generation even in the presence of proteasome inhibitors, although such inhibitors will likely alter cleavage patterns and may increase the dependence of the processing pathway on postproteasomal enzymes.

show abstract

An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses

Cited by 258 publications

References 32 publications

The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

The Selective Proteasome Inhibitors Lactacystin and Epoxomicin Can Be Used to Either Up- or Down-Regulate Antigen Presentation at Nontoxic Doses

Dynamic correlation of apoptosis and immune activation during treatment of HIV infection

Re-evaluating the Generation of a “Proteasome-Independent” MHC Class I-Restricted CD8 T Cell Epitope

Contact Info

Product

Resources

About