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Innate responses in acute HIV-1 infection

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P. Borrow1, S. Brackenridge2, O. Dibben1, D. Goldstein3, E.A. Haygreen1, B.F. Haynes3, B. Kessler4, H. Kramer4, K.J. Lavender1, A.J. McMichael2, P.J. Norris5, L. Qin6, A.R. Stacey1, E. Taylor1 and the Centre for HIV and AIDS Vaccine Immunology (CHAVI).

1The Jenner Institute, Nuffield Dept of Clinical Medicine; 2Weatherall Institute for Molecular Medicine and 4Henry Welcome building for Molecular Physiology, University of Oxford, UK; 3Duke University, Durham, NC, USA ; 5Blood Systems Research Institute, San Francisco, CA, USA ; 6Statistical Center for HIV /AIDS Research and Prevention (SCHARP), Seattle, WA, USA .

There is an urgent need for prophylactic vaccines and improved therapeutic strategies to combat infection with human immunodeficiency virus type 1 (HIV-1), the aetiological agent of AIDS . The lack of success of the antibody and T cell response-inducing HIV vaccines evaluated in clinical trials to date emphasises the need for more basic research to determine correlates of protection in this infection and identify novel strategies for HIV vaccine design. We are characterising the innate responses activated following exposure to or infection with HIV , aiming to define the contribution they make to control of early viral replication or conversely to immunopathogenic immune activation, and determine the potential for employing up- or down-modulation of selected innate responses as an effector strategy in HIV vaccine development.

Sequential plasma samples collected during the eclipse and exponential viral expansion phases from subjects acquiring HIV -1 (or for comparison, hepatitis B or C virus (HBV/HCV)) have been used to determine the nature and kinetics of the earliest systemic elevations in cytokine and chemokine levels in each infection. The first systemic evidence of immune activation in acute HIV -1 infection (AHI) was an elevation in plasma levels of acute-phase proteins, some of which have antiviral activity, during the eclipse phase. The increase in plasma viraemia in AHI was found to be associated with elevations in plasma levels of multiple cytokines and chemokines. Notably, there was comparatively little perturbation in plasma cytokine levels during the same phase of HBV infection, and a delayed response of more intermediate magnitude in acute HCV infection, indicating that rapid activation of a striking systemic cytokine cascade is not a pre-requisite for viral clearance. Although some cytokines may have beneficial effects, the intense cytokine storm in AHI may have immunopathological consequences, promoting immune activation, viral replication and CD4 + T cell loss, and could be a target for modulation by vaccine-induced responses.

Peripheral blood mononuclear cells cryopreserved at sequential timepoints from subjects undergoing HIV seroconversion have been used to address the activation and functions of innate cell subsets in AHI . Peripheral blood myeloid and plasmacytoid dendritic cell frequencies were found to be dramatically reduced from prior to the peak in plasma viraemia, then gradually increased. Some phenotypic activation of DCs was evident in AHI , and both DC subsets remained responsive to stimulation with a TLR7 /8 ligand. DCs may be an important source of immunopathological cytokine production in AHI . Proliferation of peripheral blood NK cells was observed just prior to and at the peak in plasma viraemia, and peripheral blood NK cell frequencies were elevated at this time. NK cell activation was evidenced by the presence of more class II-positive NK cells throughout acute and early infection. We are currently addressing whether NK cells expressing particular receptors eg. KIR3DS1 expand (potentially in a ligand-driven fashion) in AHI . The frequencies of both CD3 CD56 and invariant (CD1d-restricted) NKT cells in peripheral blood were reduced in AHI . Like NK cells, CD3 CD56 NKT cells were activated prior to the peak in plasma viraemia, and the proportion of CD8 cells within this population increased. CD3 +CD56 NKT cells were shown to mediate potent control of HIV replication in vitro, so like NK cells, could be an effector subset with utility in HIV vaccine design.

Together, these results suggest some novel approaches that could be employed in HIV vaccine design, including induction of regulatory T cell responses to reduce immunopathogenic cytokine production in AHI , and priming of NK or NKT populations able to recognise HIV -infected cells to mediate more efficient control of viral replication in the critical early stages of infection.

This talk is part of the Departmental Seminar Programme, Department of Veterinary Medicine series.

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