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Walker: HIV ControlĀ & Immunogen Design

OVERVIEW

HIV-1 slowly destroys the immune system of infected individuals. Remarkably, some individuals appear to be capable of controlling HIV replication for decades although they are unable to eradicate it. The mechanisms for this control are poorly understood, and such knowledge could provide key findings towards the development of an effective HIV vaccine.

The Walker-led research consortium is a collaboration among multiple scientists studying HIV controllers - persons who go on to maintain persistent control of viremia without the need for antiviral therapy - through population-based studies of immune responses, viral evolution, and host genetics. What they learn will be applied to immunogen design for a global HIV vaccine. The researchers are also studying the early events occurring following acute infection when viral load is first brought under control. The project supports an international collaboration among more than 200 clinicians who are helping to recruit these HIV controllers, with the goal of recruiting a total of 1500 persons worldwide who meet the controller definition.

The project builds on clear evidence that the immune responses to HIV as well as the pathways to immune escape are predictable, and that these are influenced by host genetics. This collaborative multinational study will provide pivotal advances to facilitate effective HIV immunogen design.

RESEARCH OBJECTIVES

  1. Use population based studies of immune responses, viral evolution, and host genetics to achieve effective immunogen design for a global HIV vaccine.
  2. Define the functionality and critical targets of the innate and adaptive cellular immune responses in situations of spontaneous control of HIV.
  3. Compare HIV controllers to progressors to determine whether they differ in terms of immune responses to HIV.

PROGRESS

This project has four interdependent elements: patient recruitment for the cohort, immune response characterization in situations of spontaneous control of HIV, identification of the predictable patterns of viral evolution in response to host immune pressures in situations of spontaneous control of HIV and the contribution of viral replicative fitness and antigen processing to viral control and immunodominance, and genome-wide association studies.

This and other HIV research is critically dependent upon the availability of well-pedigreed human blood samples, and to this end Walker research team has created an international resource to benefit science well into the future, they have completed recruitment of >1500 HIV (aviremic and viremic) controllers, and from this large cohort we have identified a select subgroup of individuals for large volume blood donations and longitudinal clinical follow-up and biological samples. They have also recruited 150 individuals with acute HIV infection.

The path forward to an HIV vaccine depends on eliciting immune responses that have a direct antiviral effect. A major accomplishment to date has been the identification of immune responses that are associated with viral control, and equally importantly the identification of a large proportion of responses that in fact appear to provide no benefit to controlling HIV, but rather serve as decoys. Those that are antiviral appear to function at least in part by forcing the virus to mutate in ways that render it less able to replicate rapidly and to cause disease. These studies have immediate and broad implications for immunogen design.

The design of an effective vaccine will require protection against all HIV strains, a scientific challenge of unprecedented proportions given the immense sequence variability fostered by the poor proofreading of the RT as new viruses are made. The Walker-led research team developed a novel technology in collaboration with the Broad Institute, which allows them to obtain detailed sequence information on the infecting strains, and the evolution of these strains under immune selection pressure. They have also developed methods to understand how virus infected cells are sensitized for recognition by the immune system, and the factors governing this process. These data are critical to define the sequence space within which HIV must exist, as they directly dictate the design of effective immunogens to counter HIV diversity. In addition, by combining functional immune response data with virus sequence data, they have identified vulnerable regions of the virus where immune selection pressure leads to reduced viral fitness, and are exploiting this information for vaccine immunogen design.

The fourth element is a genome wide association study to determine the host genetic factors associated with persistent viral control. The team has found a strong signal in the MHC region regardless of ethnic background of the subjects, and of the three billion nucleotides that make up the human genome, have found six amino acids, all related to HLA class I presentation of viral peptides, that account for the positive and negative associations with viral load. These data indicate that it is the nature of the presentation of peptide that influences outcome, and paves the way for a mechanistic understanding of what constitutes a good immune responses that can then be applied to vaccine design.

 

Grant at a Glance

Principal Investigator

Bruce Walker, MD

Grantee Institution

Massachusetts General Hospital, Boston, USA

Project Title

HIV Controllers: Implications for Immunogen Design

Grant Award

$20.6 million over 5 years, awarded September 2007

Collaborating Institutions

  • Jessen-Jessen Medical Practice, USA
  • Broad Institute, USA
  • SAIC-Frederick
  • University of KwaZulu-Natal, South Africa

External Scientific Advisory Board

  • Eric Arts, Case Western Reserve University
  • Nina Bhardwaj, New York University School of Medicine
  • Simon Frost, University of California, San Diego
  • Robert Siliciano, John Hopkins University School of Medicine
  • Amalio Telenti , University Hospital Center and University of Lausanne
  • John Wherry, The Wistar Institute
  • Jonathan Yewdell, National Institutes of Allergy and Infectious Diseases

Progress to Date

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