C5a and C5adesArg Enhance the Susceptibility of Monocyte-Derived Macrophages to HIV Infection

Abstract

Mononuclear phagocytes, which include circulating blood monocytes and differentiated tissue macrophages, are believed to play a central role in the sexual transmission of HIV infection. The ability of HIV to productively infect these cells may be influenced by action of exogenous or host-derived substances at the site of viral entry. Given the potent capacities of inflammatory mediators to stimulate anaphylatoxic and immunomodulatory functions in mucosa, the effects of complement-derived anaphylatoxins on the susceptibility of monocytes and monocyte-derived macrophages (MDM) to HIV-1 infection were examined. In our in vitro system, the susceptibility to infection was up to 40 times increased in MDM that had been exposed to C5a or C5adesArg, but not to C3a or C3adesArg, for 2 days before adding of virus. By contrast, the treatment with complement anaphylatoxins did not affect HIV replication in fresh monocytes. Stimulatory effect of C5a and its desArg derivative on HIV infection correlated with the increase of TNF-α and IL-6 secretion from MDM. All these functional effects of C5a and C5adesArg were reversible by treatment of cells with the mAb that functionally blocks C5aR. Taken together, these results indicate that C5a and C5adesArg may increase the susceptibility of MDM to HIV infection through stimulation of TNF-α and IL-6 secretion from these cells.

Production of recombinant C5a from rainbow trout (Oncorhynchus mykiss): role in leucocyte chemotaxis and respiratory burst

“…C5a is significantly more powerful than C3a in inducing biologically relevant responses [2]. C5a plays an important role in promoting (1) chemotaxis to a variety of leucocytes, including neutrophils and macrophages [3e5]; (2) activation of the respiratory burst in phagocytes [6]; (3) the expression of tumor necrosis factor (TNF)-a and interleukin (IL)-6 in monocytederived macrophages [7] as well as the expression of IL-1b, RANTES and IL-8 in umbilical vein endothelial cells [8]; (4) production of prostaglandins and eicosanoids [9]; (5) release of histamine by mast cells and basophils [10,11]; (6) up-regulation of Fc, complement receptor type 3 (CR3) [12,13] and P-selectin [14]. C5a has also been demonstrated to have an influence in adaptive immune responses.…”

C5aR-dependent cell activation by physiological concentrations of C5a-desArg: Insights from a novel label-free cellular assay

“…Both C5a and C5a desArg bear similar efficacy at inducing histamine and leukotriene C4 release by primed basophils (8), calcium mobilization in mouse peritoneal macrophages (46) and neutrophil-mediated platelet aggregation (47). Further, both proteins are able to prime macrophages and enhance their susceptibility to HIV infection (48). Therefore, C5a desArginduced cell responses are critically dependent on the type of cell and response studied (7)(8)(9)(10).…”

A Novel Role for the Receptor of the Complement Cleavage Fragment C5a, C5aR1, in CCR5-Mediated Entry of HIV into Macrophages

“…This effect could be blocked using a C5aR1-specific mAb. 12 In search for mechanisms underlying this effect, the authors found that C5a increased TNF-a and IL-6 production from MDM. Furthermore, they have shown that specific targeting of C5aR1, using the same mAb that we have used in our study (S5/1), inhibited the C5a-mediated increase of TNF-a or IL-6, demonstrating that C5aR1 signaling is critical for the effect.…”

“…11 Previous studies have shown that C5a can enhance the infection of MDM and T cells indirectly through the production of interleukin (IL)-6 and tumor necrosis factor (TNF)-a and the attraction of DCs. 10,12 Complementmediated enhancement of HIV infection was also described for CD4 cells. 13 Interestingly, C5aR1 forms heterodimers with the chemokine receptor CCR5, a major coreceptor for viral entry for R5 strains 14 in a rat basophilic leukemia cell line.…”