Activation of acute phase reactants may represent a very early line of anti-viral defense in HIV-1 infection, since A-SAA, AAT and a C-terminal peptide derived from AAT (referred to as VIRIP) were each shown to exert anti-viral activity in vitro [10, 19, 25, 26] (Fig. 6A,B) . However, not all acute phase proteins that are induced in response to inflammation have anti-viral properties as was observed with CRP ( Fig. 6C) , which was also elevated systemically in plasma of some donors prior to viremia (data not shown). We found selective inhibition of HIV-1 infection of MDDCs but not PBMCs by A-SAA. Its ability to inhibit HIV-1 replication was previously proposed to be mediated by downregulation of CCR5 expression [19] . The capacity to inhibit R5 virus replication in MDDCs but not PBMCs may thus be due to the fact that MDDCs express only low levels of CCR5, whereas CCR5 expression on CD4 + T cells is much higher. It is unlikely that the inhibitory effects of A-SAA are limited to specific pathogens only, as this acute phase reactant was described to be up-regulated in a number of pathological processes [17] including inflammation and diverse bacterial and viral infections [27, 28, 29] . Consistent with this, we observed marked elevation of A-SAA in plasma panels from donors acutely-infected with HCV. Notably, A-SAA has been shown to mediate antiviral activity against this viral pathogen too, an effect proposed to be mediated by mechanisms distinct from its inhibitory effect on HIV-1 infection [30, 31] . In acute HCV infection, A-SAA induction may be stimulated as a consequence of viral replication in the liver, and the associated cytokine response. In acute HBV infection little A-SAA elevation was observed. This may relate to the different Fig. S1 ) before and during viremia. Viral load and T 0 are as described previously [14] . Top panels: viral load; second and third panels: peak intensities of mass peaks 2178 Da and 2213 Da normalized to the corresponding peak intensities observed for the first time point of 64012; bottom panels: relative peak intensities of mass peaks 1555 and 2552 that were used as standards, illustrating use of comparable MS acquisition conditions for all time points. The arrows in the middle and bottom panels indicate viremic time points. doi:10.1371/journal.ppat.1000893.g002 [14] . The solid circles show A-SAA protein levels. Subject-specific background levels of A-SAA (dotted grey lines) and the 90% prediction interval (threshold for defining a significant elevation, black lines) were calculated as described in the methods section. 15 out of 19 subjects show a significantly elevated A-SAA level before the first detectable viral load. (B). A-SAA and C-SAA protein levels in sequential plasma samples from 10 donors acquiring HIV-1 infection as assessed using anti-A-SAA and anti-C-SAA immunoblotting. The two sets of blots are positioned replication kinetics of HBV as compared to HIV-1 and HCV, and/or the relatively muted cytokine response activated in acute HBV infection [14] .