Value of consultation in establishing a public health research network: lessons from APPRISE.

OBJECTIVES: To understand the challenges and benefits of an extensive consultation process relating to the establishment and ongoing funding of a novel, disseminated national research network for infectious disease preparedness. METHODS: We used a two-part modified Delphi process to identify and rank factors relating to the consultation process across the different stages of setting up a new research network. RESULTS: Research priorities for the new research network remained the same following consultation with a broad range of stakeholders. Broad networking and the establishment of a nationally recognised preparedness research network were clearly identified as the consultation's key strengths. The need for ongoing management of diverse expectations, particularly between researchers and public health practitioners, are clear challenges. Clarity on the distinct roles of researchers and decision makers are necessary to integrate research into a translational pathway. Researcher expectations for investigator-driven detailed inquiry must be balanced with expectations of routine public health activities and decision making. CONCLUSIONS: Consultation had a clear benefit for the development of a complex public health network with a focus on policy translation. Ongoing challenges include managing diverse expectations and recognising the need for continuing relationship management. Understanding the strengths and limitations of consultation to enable ongoing funding should inform the development of further collaborative research networks in multidisciplinary and translational contexts in health.

Rapid viral escape at an immunodominant simian-human immunodeficiency virus cytotoxic T-lymphocyte epitope exacts a dramatic fitness cost.

Escape from specific T-cell responses contributes to the progression of human immunodeficiency virus type 1 (HIV-1) infection. T-cell escape viral variants are retained following HIV-1 transmission between major histocompatibility complex (MHC)-matched individuals. However, reversion to wild type can occur following transmission to MHC-mismatched hosts in the absence of cytotoxic T-lymphocyte (CTL) pressure, due to the reduced fitness of the escape mutant virus. We estimated both the strength of immune selection and the fitness cost of escape variants by studying the rates of T-cell escape and reversion in pigtail macaques. Near-complete replacement of wild-type with T-cell escape viral variants at an immunodominant simian immunodeficiency virus Gag epitope KP9 occurred rapidly (over 7 days) following infection of pigtail macaques with SHIVSF162P3. Another challenge virus, SHIVmn229, previously serially passaged through pigtail macaques, contained a KP9 escape mutation in 40/44 clones sequenced from the challenge stock. When six KP9-responding animals were infected with this virus, the escape mutation was maintained. By contrast, in animals not responding to KP9, rapid reversion of the K165R mutation occurred over 2 weeks after infection. The rapidity of reversion to the wild-type sequence suggests a significant fitness cost of the T-cell escape mutant. Quantifying both the selection pressure exerted by CTL and the fitness costs of escape mutation has important implications for the development of CTL-based vaccine strategies.