Evaluation of the effects of phagocytosis in apoptotic cells on the response of the virus of human immunodeficiency virus (HIV) type 1
Clearance of apoptotic cells increases macrophage secretion of antiinflammatory mediators and might modulate viral replication in human immunodeficiency virus (HIV) type 1-infected macrophages. To study this, primary macrophages were infected with HIV-1 and exposed to apoptotic cells, and we found that this interaction potently enhanced HIV-1 growth. Viral replication was preceded by increased secretion of TGF-amp;#61538;1, and partially reverted by anti-TGF-amp;#61538;1 antibodies. Moreover, anti-TGF-amp;#61538;1 antibodies inhibited HIV-1 replication in macrophages not exposed to apoptotic cells and the addition of TGF-amp;#61538;1 amplified HIV-1 replication in macrophages from low TGF-amp;#61538;1 producers, suggesting that TGF-amp;#61538;1 favors HIV-1 replication. The inhibition of cyclooxygenase 2 (COX-2), a key enzyme of the pathway of PGE2 production, ablated the viral growth amplification triggered upon the uptake of apoptotic cells by HIV-1-infected macrophages and addition of PGE2 to HIV-1-infected macrophages enhanced viral replication. The use of a PAF receptor antagonist decreased HIV-1 replication in infected macrophages, and the addition of PAF to these cells amplified viral growth. The peptide Arg-Gly-Asp-Ser inhibited the uptake of apoptotic cells and the subsequent enhancement of HIV-1 replication, suggesting the participation of an integrin receptor. The participation of the integrin amp;#61537;Vamp;#61538;3 (vitronectin receptor, VnR) in this phenomenon was confirmed by using and anti-amp;#61537;V monoclonal antibodies (MAbs). The antagonist MAb anti-amp;#61537;Vamp;#61538;3 neutralized the enhancement of HIV-1 growth mediated by apoptotic cells, and the agonist MAb anti-amp;#61537;V potently augmented viral replication in HIV-1-infected macrophages. Our findings suggest that TGF-amp;#61538;1, PAF and PGE2, as well as stimulation of VnR, favor HIV-1 replication in macrophages and that the clearance of apoptotic cells by HIV-1-infected macrophages might contributes to persistent viremia in patients infected with HIV-1.
Advisor:Dumith Chequer Bou-Habib
School:Faculdades Oswaldo Cruz
Source Type:Master's Thesis
Keywords:HIV-1 Viral Replication Phagocytosis
Date of Publication:11/24/2004