received salary support from a Jenner Institute senior fellowship. are Jenner Institute Investigators, and P.B. was supported by an MRC New Investigator Award and is supported by the NIHR Biomedical Research Centre, Oxford. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.įunding: This work was supported by funding from the Division of AIDS, NIAID, NIH grant AI067854. Received: OctoAccepted: ApPublished: May 6, 2010Ĭopyright: © 2010 Kramer et al. Douek, NIH/NIAID, United States of America (2010) Elevation of Intact and Proteolytic Fragments of Acute Phase Proteins Constitutes the Earliest Systemic Antiviral Response in HIV-1 Infection. 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.Ĭitation: Kramer HB, Lavender KJ, Qin L, Stacey AR, Liu MKP, di Gleria K, et al. We describe increases in plasma levels of acute-phase reactants and proteolytically processed fragments that have anti-viral activity in vitro. 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. 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. ![]() 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. Insights gained into the mechanism of action of acute-phase reactants and other innate molecules against HIV and how they are induced could be exploited for the future development of more efficient prophylactic vaccine strategies.Īcquired 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. Our results provide evidence for a first wave of host anti-viral defense occurring in the eclipse phase of AHI prior to systemic activation of other immune responses. Both A-SAA and VIRIP have anti-viral activity in vitro and quantitation of their plasma levels indicated that circulating concentrations are likely to be within the range of their inhibitory activity. Furthermore, a proteolytic fragment of alpha–1-antitrypsin (AAT), termed virus inhibitory peptide (VIRIP), was observed in plasma coincident with viremia. Induction of acute phase protein serum amyloid A (A-SAA) occurred as early as 5–7 days prior to the first detection of plasma viral RNA, considerably prior to any elevation in systemic cytokine levels. Analysis of unique plasma donor panels spanning the eclipse and viral expansion phases revealed very early alterations in plasma proteins in AHI. ![]() The ability of selected factors found to be elevated in the plasma during AHI to inhibit HIV-1 replication was analyzed using in vitro PBMC and DC infection models. A proteomics-based screen was performed on a cohort from whom samples were available at time points prior to the earliest positive HIV detection. During this time frame, components of the innate immune system such as macrophages and DCs, NK cells, β-defensins, complement and other anti-microbial factors, which have all been implicated in modulating HIV infection, may play particularly important roles. The earliest immune responses activated in acute human immunodeficiency virus type 1 infection (AHI) exert a critical influence on subsequent virus spread or containment.
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