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SUMMARY:Innate responses in acute HIV-1 infection - Dr Persephone Borrow\,
  Viral Immunology\, The Jenner Institute\, Oxford
DTSTART:20091014T153000Z
DTEND:20091014T163000Z
UID:TALK20413@talks.cam.ac.uk
CONTACT:Suzy Blows
DESCRIPTION: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).\n\n1The Jenner Ins
 titute\, Nuffield Dept of Clinical Medicine\; 2Weatherall Institute for Mo
 lecular Medicine and 4Henry Welcome building for Molecular Physiology\, Un
 iversity of Oxford\, UK\; 3Duke University\, Durham\, NC\, USA\; 5Blood Sy
 stems Research Institute\, San Francisco\, CA\, USA\; 6Statistical Center 
 for HIV/AIDS Research and Prevention (SCHARP)\, Seattle\, WA\, USA.\n\nThe
 re is an urgent need for prophylactic vaccines and improved therapeutic st
 rategies 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 o
 f protection in this infection and identify novel strategies for HIV vacci
 ne 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 immunopathoge
 nic immune activation\, and determine the potential for employing up- or d
 own-modulation of selected innate responses as an effector strategy in HIV
  vaccine development.\n\nSequential plasma samples collected during the ec
 lipse 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 c
 ytokine and chemokine levels in each infection. The first systemic evidenc
 e of immune activation in acute HIV-1 infection (AHI) was an elevation in 
 plasma levels of acute-phase proteins\, some of which have antiviral activ
 ity\, during the eclipse phase. The increase in plasma viraemia in AHI was
  found to be associated with elevations in plasma levels of multiple cytok
 ines 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\, i
 ndicating 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 immunopat
 hological consequences\, promoting immune activation\, viral replication a
 nd CD4+ T cell loss\, and could be a target for modulation by vaccine-indu
 ced responses.\n\nPeripheral blood mononuclear cells cryopreserved at sequ
 ential timepoints from subjects undergoing HIV seroconversion have been us
 ed 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 TL
 R7/8 ligand. DCs may be an important source of immunopathological cytokine
  production in AHI. Proliferation of peripheral blood NK cells was observe
 d 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 evi
 denced by the presence of more class II-positive NK cells throughout acute
  and early infection. We are currently addressing whether NK cells express
 ing particular receptors eg. KIR3DS1 expand (potentially in a ligand-drive
 n fashion) in AHI. The frequencies of both CD3+CD56+ and invariant (CD1d-r
 estricted) NKT cells in peripheral blood were reduced in AHI. Like NK cell
 s\, CD3+CD56+ NKT cells were activated prior to the peak in plasma viraemi
 a\, and the proportion of CD8+ cells within this population increased. CD3
 +CD56+ NKT cells were shown to mediate potent control of HIV replication i
 n vitro\, so like NK cells\, could be an effector subset with utility in H
 IV vaccine design. \n\nTogether\, these results suggest some novel approac
 hes 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-infec
 ted cells to mediate more efficient control of viral replication in the cr
 itical early stages of infection.\n
LOCATION:Lecture Theatre 1\, Department of Veterinary Medicine
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