Walker Vaccine Discovery Consortium

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. To date, 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 VDC 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 2000 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:

The researchers have expanded the International HIV controllers consortium to include over 200 HIV providers and scientists that refer subjects to our study. This VDC has recruited over 1300 HIV-infected controllers.
 
The VDC is conducting a statistical analysis of more than 1300 subjects to define the genetic factors that impact durable control of HIV. Their analysis demonstrates associations between single nucleotide polymorphisms (SNPs) in the major histocompatibility complex and viral load set point after acute infection.

A key question is whether HIV-controllers have different T-cell responses than progressors. The VDC researchers found that CD8+ T-cells from HIV controllers preferentially target the HIV Gag protein over other proteins, whereas responses are more broadly distributed in persons with progressive infection.

Compared to progressors, controllers had significantly more CD4+ and CD8+ T cells secreting the cytokines interferon-gamma and interleukin-2, as well as lower HIV-specific neutralizing antibody responses.

Researchers in the Walker VDC have also discovered that specific types of natural killer (NK) cells are expanded during the acute phase of HIV infection. NK cells are part of the innate immune response and they act as quality control for all cells, including dendritic cells, by eliminating defective ones. This VDC is exploring how HIV’s impact on NK cells might affect the progression of infection.

Another key question is whether the viruses infecting HIV controllers may differ from those infecting progressors. Here the Walker VDC has discovered that individuals who control HIV exhibit unique mutations in targeted CD8 epitopes and that these viruses are deficient in their ability to replicate. These data suggest that strong immune responses in controller subjects may have selected for uniquely deleterious mutations that contribute to sustained control of HIV, helping to identify key targets for vaccine development.

The Walker VDC investigators have also identified viral sequence motifs within and around key CD8 T cell epitopes that contribute to the efficiency of HIV epitope processing. They are investigating levels of antigen processing activities in controllers and progressors and the efficiency with which epitopes are processed in these groups of individuals.