Much of our current picture of events in the eclipse and earliest viremic phases of acute HIV-1 infection is derived from in vitro studies and work carried out in non-human primate simian immunodeficiency virus (SIV) infection models, as the critical initial stages of infection are very difficult to study in humans. The availability of plasma sample series collected over a time-frame spanning the eclipse and viral expansion phase of HIV infection provide a unique opportunity to gain insight into the systemic activation of immune responses during this time. Previous reports have quantified an array of cytokines and markers of apoptosis in plasma panels and described a massive systemic ''cytokine storm'' occurring during the viral ramp-up phase, associated with an increase in plasma levels of apoptotic microparticles [12, 13, 14] . Importantly however, no systemic elevation in apoptosis markers or cytokine levels was detected during the eclipse phase when virus is being amplified at local infection sites prior to systemic dissemination. In this study, we used a proteomics-based approach combined with biochemical and cell biological assays to characterize factors that are elevated in plasma during the earliest stages of acute HIV-1 infection in humans. We describe increases in plasma levels of acute-phase reactants and proteolytically processed fragments that have anti-HIV activity during the eclipse phase prior to detection of HIV viremia or the first increases in systemic cytokine levels, which may represent the earliest systemic host antiviral response activated following infection.