Acquired immune deficiency syndrome (AIDS) remains a major health problem worldwide, affecting predominantly the adult population in the western world and in developing countries in particular. Despite a tremendous effort to develop a cure or a vaccine that confers protection against human immunodeficiency virus (HIV-1) infection, this has not been achieved in a satisfactory manner to date. Recent research efforts have suggested that the earliest immune responses activated after exposure to the virus have an influence on virus spread, containment and disease progression. In this study, a panel of donors who provided plasma samples collected over a time-frame spanning the period before and immediately after detection of HIV-1 infection permitted an insight into the activation of the earliest systemic immune responses. We describe increases in plasma levels of acute-phase reactants and proteolytically processed fragments that have anti-viral activity in vitro. These inductions occur prior to detection of HIV-1 virus in the blood and before the first increases in systemic cytokine levels, which may represent the earliest systemic host antiviral response activated following infection.