Abstract
BackgroundHIV-1 Protease Inhibitors, namely PIs, originally designed to inhibit HIV-1 aspartic protease, can modulate the immune response by mechanisms largely unknown, and independent from their activity on viral replication. Here, we analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response.Methodology/Principal FindingsMonocytes from healthy donors were isolated and induced to differentiate in vitro in the presence or absence of saquinavir, ritonavir, nelfinavir, indinavir or amprenavir (sqv, rtv, nlfv, idv, apv, respectively). These drugs demonstrated a differential ability to sustain the generation of immature DCs (iDCs) with an altered phenotype, including low levels of CD1a, CD86, CD36 and CD209. DCs generated in the presence of rtv also failed to acquire the typical phenotype of mature DCs (mDCs), and secreted lower amounts of IL-12 and IL-15. Accordingly, these aberrant mDCs failed to support activation of autologous Natural Killer (NK) cells, and resulted highly susceptible to NK cell-mediated cytotoxicity.Conclusions/SignificanceOur findings uncover novel functional properties of PIs within the DC-NK cell cross-talk, unveiling the heterogeneous ability of members of this class drugs to drive the generation of atypical monocyte-derived DCs (MDDCs) showing an aberrant phenotype, a failure to respond appropriately to bacterial endotoxin, a weak ability to prime autologous NK cells, and a high susceptibility to NK cell killing. These unexpected properties might contribute to limit inflammation and viral spreading in HIV-1 infected patients under PIs treatment, and open novel therapeutical perspectives for this class drugs as immunomodulators in autoimmunity and cancer.
Highlights
HIV-1 Protease Inhibitors, that are included in the Highly Active Antiretroviral Therapy (HAART) of AIDS, has been designed to inhibit HIV-1 aspartic protease [1,2]
All of them demonstrated the ability to affect the expression of CD209, a molecule involved in the binding, and spreading of the HIV-1 virions to T-lymphocytes [24]
All together these findings reveal a differential ability of PIs to interfere with differentiation program of monocytes and to drive the generation of immature Dendritic cells (DCs) (iDCs) with remarkable alterations in their phenotype
Summary
HIV-1 Protease Inhibitors, that are included in the Highly Active Antiretroviral Therapy (HAART) of AIDS, has been designed to inhibit HIV-1 aspartic protease [1,2]. Similar immunosuppressive effects have been reported in mouse infected by lymphocytic virus [5] In this experimental model, ritonavir treatment limited the anti-viral T-cell cytotoxicity and prevented tissues damage induced by CD8+ T-cells. Several studies have shown the ability of PIs to interfere with activation programs of human primary T-cells It has been demonstrated the effectiveness of rtv to inhibit the secretion of tumor necrosis factor alpha (TNF-a), and decrease the spontaneous and activationinduced susceptibility to apoptosis of uninfected peripheral mononuclear cells [4]. Pre-treatment with idv can exert similar immunosuppressive effects on mononuclear cells isolated from peripheral blood of HIV-1+, or healthy individuals [13]. We analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
