The availability of sequential samples from plasma donors who became infected with HIV-1 provides a unique opportunity to study changes in plasma in the eclipse and viral expansion phases of acute infection. Recent studies described the induction of a ''cytokine storm'' and massive cellular apoptosis during the phase of exponential viral replication [12, 13, 14] . Here a proteomicsdriven approach was used to demonstrate for the first time that acute phase proteins, some of which exhibit antiviral activity, are induced systemically even prior to the first detection of viremia and also before any detectable increase in plasma cytokine levels. The factors elevated included A-SAA, a protein primarily synthesized by cells in the liver, high-level production of which is known to be induced during the acute phase response to infection, trauma or stress by pro-inflammatory cytokines including TNF-alpha, IL-6 and IL-22 [21] . Notably, A-SAA was frequently elevated with biphasic kinetics in the plasma of subjects acquiring HIV-1 infection, an initial elevation occurring during the eclipse phase and a second elevation during the viral ramp-up phase. The latter was temporally coincident with elevations in circulating levels of multiple pro-inflammatory cytokines [14] and likely reflected a hepatic response to this systemic stimulus. The initial elevation in plasma A-SAA levels was found to occur significantly prior to detection of viral RNA in the plasma, well before any systemic elevations are detected in plasma cytokine/ chemokine levels [14] . Following sexual transmission of HIV-1, virus replicates in the local genital or rectal mucosa, then spreads to the draining lymph nodes and subsequently to the gutassociated lymphoid tissue (GALT) [22] . The mechanism by which acute phase protein production is triggered during this process is currently unknown, but it may involve transfer of inductive factors to the liver (including pro-inflammatory cytokines produced at local sites of viral replication), triggering production of acute phase reactants prior to widespread virus dissemination and systemic increases in cytokine levels. Alternatively, A-SAA can be produced at extra hepatic sites: A-SAA expression has been reported in macrophages, adrenal glands, kidney and intestine, albeit at lower levels as compared to hepatocytes [17] . The initial burst of A-SAA levels may also contribute to the subsequent ''cytokine storm'' observed later at the systemic level, since A-SAA was shown to induce an array of immunomodulatory cytokines including of the Th1-type in monocytes, macrophages and lymphocytes [23, 24] .