title: Advanced glycation end products inhibit both infection and transmission in trans of HIV-1 from monocyte-derived dendritic cells to autologous T cells.
abstract: Highly active antiretroviral therapy is associated with carbohydrate metabolic alterations that may lead to diabetes. One consequence of hyperglycemia is the formation of advanced glycation end products (AGEs) that are involved in diabetes complications. We investigated the impact of AGEs on the infection of monocyte-derived dendritic cells (MDDCs) by HIV-1 and the ability of MDDCs to transmit the virus to T cells. We showed that AGEs could inhibit infection of MDDCs with primary R5-tropic HIV-1(Ba-L) by up to 85 ± 9.2% and with primary X4-tropic HIV-1(VN44) by up to 60 ± 8.5%. This inhibitory effect of AGEs was not prevented by a neutralizing anti-receptor for advanced glycation end products (anti-RAGE) Ab, demonstrating a RAGE-independent mechanism. Moreover, AGEs inhibited by 70-80% the transmission in trans of the virus to CD4 T cells. Despite the inhibitory effect of AGEs on both MDDC infection and virus transmission in trans, no inhibition of virus attachment to cell membrane was observed, confirming that attachment and transmission of the virus involve independent mechanisms. The inhibitory effect of AGEs on infection was associated with a RAGE-independent downregulation of CD4 at the cell membrane and by a RAGE-dependent repression of the CXCR4 and CCR5 HIV-1 receptors. AGEs induce the secretion of proinflammatory cytokines IL-6, TNF-α, and IL-12, but not RANTES or MIP-1α, and did not lead to MDDC maturation as demonstrated by the lack of expression of the CD83 molecule. Taken together, our results suggest that AGEs can play an inhibiting role in HIV-1 infection in patients who accumulate circulating AGEs, including patients treated with protease inhibitors that developed diabetes.
authors.affiliation: INSERM Unité 743, Centre de Recherche des Cordeliers, Paris F-75006, France.
authors.forename: Nadine
authors.initials: N
authors.lastname: Nasreddine
authors.forename: Chloé
authors.initials: C
authors.lastname: Borde
authors.forename: Joël
authors.initials: J
authors.lastname: Gozlan
authors.forename: Laurent
authors.initials: L
authors.lastname: Bélec
authors.forename: Vincent
authors.initials: V
authors.lastname: Maréchal
authors.forename: Hakim
authors.initials: H
authors.lastname: Hocini
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000821:virology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000821:virology*; D015536:Down-Regulation; D017127:Glycation End Products, Advanced / Q000276:immunology / Q000502:physiology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000276:immunology / Q000378:metabolism; D053585:Virus Attachment; D053586:Virus Internalization; D014779:Virus Replication; D000097802:CD83 Antigen
chemical_list: D057134:Antibodies, Neutralizing; D015703:Antigens, CD; D015704:CD4 Antigens; D016207:Cytokines; D017127:Glycation End Products, Advanced; D007136:Immunoglobulins; D008562:Membrane Glycoproteins; D000067759:Receptor for Advanced Glycation End Products; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011971:Receptors, Immunologic; D000097802:CD83 Antigen; C527276:CXCR4 protein, human