IgG Opsonization of HIV Impedes Provirus Formation in and Infection of Dendritic Cells and Subsequent Long-Term Transfer to T Cells

Abstract

Already at initial phases of infection, HIV is coated with complement fragments. During the chronic phase, when HIV-specific IgGs appear, the virus circulates immune complexed with IgG and complement. Thus, we studied the interaction of dendritic cells (DCs) and DC-T cell cocultures with complement (C)-opsonized and C-IgG-opsonized HIV. HIV infection of monocyte-derived DCs and circulating BDCA-1-positive DCs was significantly reduced upon the presence of virus-specific but non-neutralizing IgGs. DCs exposed to C-Ig-HIV or IgG-opsonized HIV showed an impaired provirus formation and p24 production and a decreased transmission rate to autologous nonstimulated T cells upon migration along a chemokine gradient. This reduced infectivity was also observed in long-term experiments, when T cells were added delayed to DCs exposed to IgG-coated HIV without migration. Similar kinetics were seen when sera from HIV-1-infected individuals before and after seroconversion were used in infection assays. Both C- and C-IgG-opsonized HIV were captured and targeted to a tetraspanin-rich endosome in immature DCs, but differed with respect to MHC class II colocalization. The reduced infection by IgG-opsonized HIV is possibly due to interactions of virus-bound IgG with FcγRIIb expressed on DCs. Therefore, the intracellular fate and transmission of immune-complexed HIV seems to differ depending on time and opsonization pattern.

Dendritic Cells Derived from Hemozoin-Loaded Monocytes Display a Partial Maturation Phenotype that Promotes HIV-1 Trans-Infection of CD4+ T Cells and Virus Replication

“…Because circulating DCs represent ,1% of the total cell population in human peripheral blood, we used monocytes known to be a usual progenitor for the in vitro generation of iDCs when cultured with a cytokine mixture made of GM-CSF and IL-4 (26)(27)(28)(29). For the purpose of our study, monocytes were separated from PBMCs by cell adherence as described previously (30,31). As expected, when cultured in vitro in the presence of GM-CSF and IL-4, monocytes acquire some specific surface markers and features of immature myeloid DCs (e.g., DC-SIGN and CD1a), while losing markers typical of monocytes and macrophages, such as CD14 (data not shown) (27,32,33).…”

Innate Immune Responses in HIV Infection

“…By clustering T cells, DCs may both activate antiviral immunity as well as facilitate spread of the virus. In vitro experiments showed that DCs efficiently capture and transfer HIV to T cells and initiated a vigorous infection (Pope et al, 1995;McDonald et al, 2003;Pruenster/Wilflingseder et al, 2005;Wilflingseder et al, 2007). These experiments imply that in vivo HIV exploits DCs at mucosal sites as shuttles to CD4 + T cells in the lymph nodes.…”

Role of Dendritic Cell Subsets on HIV-Specific Immunity

“…During acute infection multiple humoral and cellular players, including cytokines, complement, acute-phase proteins, DC, macrophages, and natural killer (NK) cells, that co-operate to generate an efficient defense against infection, are activated. HIV-1 spontaneously triggers the complement system also in absence of specific Abs by interactions of gp41 with C1q [38][39][40][41]. Due to regulators of complement activation (RCAs) in the viral surface, HIV-1 is very efficiently protected against virolysis, which normally occurs due to MAC (membrane attack complex) formation and destruction of pathogens or infected cells.…”