|Kinetics of the earliest innate and adaptive responses in acute HIV-1 infection Nat. Rev. Immunol. 10: 11, 2010|
|The systemic cytokine storm induced in acute HIV-1 infection J. Virol. 83: 3719, 2009|
Professor of Viral Immunology
There is an urgent need for vaccines to combat infection with human immunodeficiency virus type 1 (HIV-1), persistent infection with which is associated with development of an acquired immunodeficiency syndrome (AIDS) currently responsible for ~3 million deaths per year worldwide. The key goals of prophylactic HIV vaccine strategies are to try to block the establishment of infection via induction of broadly-neutralising antibody (bNAb) responses, and to induce rapidly-acting immune responses able to modulate the events in early infection that are now known to be critical determinants of the subsequent disease course: establishment, local expansion and dissemination of infection, exponential acute viral replication (resulting in depletion of the memory CD4+ T cell pool), followed by partial containment of viral replication and establishment of a setpoint persisting viral load. The major roadblocks currently hampering rational HIV vaccine design are the lack of understanding of how to elicit HIV-1 bNAbs; and the need to define the component(s) of an immune response able to intervene and mediate protection during the critical initial stages of infection.
One series of projects in the group aim to facilitate the development of vaccination strategies capable of eliciting HIV-1 bNAbs via i) induction of CD4 T cell responses that provide optimal help for the generation of appropriate B cell responses, and ii) transient reduction of regulatory constraints on germinal centre responses to enable generation of B cell responses to epitopes on the HIV envelope glycoprotein with similarity to host determinants. The relationship between the nature and specificity of the CD4 T cell response and development of bNAbs targeting particular viral epitopes in HIV-infected individuals is being explored; and the relative ability of different vaccination platforms to elicit CD4 T follicular helper cell responses is being determined. In addition, abnormalities in regulatory cell subsets induced during HIV-1 infection that enable bNAb development in a small proportion of infected individuals are being characterised to inform the design of strategies for transiently modifying regulatory constraints on bNAb development at the time of vaccination.
Innate responses can be activated very rapidly in response to pathogen exposure or infection, and play important roles both in containment of early pathogen replication and promotion of induction of the adaptive response. In acute HIV infection, innate immune responses may also mediate immunopathological effects by driving immune activation and facilitating virus replication and spread. We thus hypothesise that the nature of the innate response in acute HIV-1 infection may be among the factors involved in determining the prognostically important setpoint viral load; and that aspects of innate responses may contribute to the resistance exhibited by certain individuals to full, seropositive HIV infection despite repeated viral exposure. A key implication of this is that modulation of innate responses could represent a novel approach to complement existing HIV vaccine strategies. A second series of projects in the group are addressing these hypotheses, focusing in particular on the role of type 1 interferons and other innate cytokines in blocking HIV-1 replication early after transmission, and the contribution of natural killer cells to HIV-1 control. We are also carrying out some comparative analysis of innate responses in the acute phase of other virus infections.
T cell responses play a key role in the elimination of many established virus infections, and multiple lines of evidence suggest that virus-specific CD8+ T cells make an important contribution to both the initial containment of primary viraemia and subsequent control of ongoing viral replication during HIV infection. Prophylactic and therapeutic strategies to combat HIV infection are thus also being designed to invoke this arm of the immune response. However the primary HIV-specific CD8 T cell response remains relatively poorly characterised, and how aspects of this response and its subsequent maintenance or evolution may impact on the initial and longer-term efficiency of control of virus replication are not well understood. A third series of projects within the group are analysing the relationship between qualitative aspects of the virus-specific CD8+ T cell response induced in primary HIV infection, the extent and kinetics of viral mutational escape from CD8+ T cell control, the fitness of the founder virus and its reduction as a consequence of acquisition of T cell escape mutations, and the subsequent efficiency of control of viral replication. We are also addressing the possibility that unconventional CD8+ T cell responses targeting novel HIV-1 epitopes could be employed to enhance vaccine-mediated HIV-1 control, and are using immunopeptidomic approaches to define epitope types presented on HIV-infected cells.
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