NHLBI Working Group
HIV-Associated Lung Infections: Bridging Innate and Acquired Immunity

Executive Summary
September 27-28, 2005

The National Heart, Lung, and Blood Institute (NHLBI) convened a meeting of investigators on September 27-28, 2005 , in Bethesda Maryland. This group of experts in immunology, pulmonology, animal models, molecular biology, mathematical modeling, HIV, TB, and other HIV-related lung infections reviewed current thinking about the roles and interactions between innate and acquired immunity in HIV-related lung infections, discussed strategies for advancing the field, and provided recommendations for future research.

The group concluded that it is important to encourage continued connection and interaction of basic scientists with clinical collaborators and especially research involving preclinical steps leading to translational and clinical research, which the group termed “Transition to Translation.” They emphasized the importance of the parallel and synergistic scientific approaches of “reductionism and reconstructionism;” both of which are essential and benefit from each other. The group stressed the need for new strategies for immune modulation to balance tissue (lung) damage versus the immune response, since either too little or too much host response to any infection can be detrimental. Lack of access to inexpensive immune modulatory agents, including biological agents and small molecules, was noted as an obstacle to progress. Another important obstacle identified was the lack of validated animal models and insufficient access to existing models, especially primate models of disease. These are very expensive and it is important to develop programs to get the most out of these valuable resources.

General Recommendations of the group include:

• Encourage continued connection and interaction between basic scientists, equipped to find testable mechanisms, and clinical collaborators able to validate insights from animal models in human studies through use of initiatives geared to promoting collaborative studies.
• Promote use of innovative modeling techniques (including mathematical modeling) which should be supportive to predict outcomes of clinical trials and interventions.
• Develop a clinical specimen repository for samples related to HIV and associated opportunistic infections of the lung. This could include sputum, BAL, lung biopsies, blood, plasma, serum, or DNA resources. To be effective such a repository requires appropriate clinical phenotyping and support by sophisticated databases and archiving systems. These samples are currently often discarded as clinical waste or are maintained in small private collections.
• Foster further research on macrophages and dendritic cells in lung infection, as they are thought to be the key cells bridging innate and adaptive immunity.
• Encourage additional research that focuses on genetic predictors of response to a given microbe, in particular to the relative balance between infection and immunity.
• Encourage studies targeted to the host-microbe interface that triggers both innate and adaptive immunity. This would be important for both non-HIV as well as HIV associated lung infection.
• Encourage research to develop interventions, e.g., novel chemotherapeutic approaches targeting immune modulation in HIV and HIV-associated opportunistic infections.
  • This could be a fertile area of investigation using funding mechanisms geared to high risk, high impact exploratory research, such as the R21 grant.
  • The committee requested NIH assistance in getting inexpensive access to immune modulatory agents, including biological agents and small molecules to speed research in developing these approaches. NIH should “weigh-in” with the private sector to provide ready access to expensive reagents for studies of immune modulatory therapy.
• Emphasize development of new models of pulmonary infection that mimic human disease. Animal models should be verified against human tissues from the relevant disease human disease state.
• Develop initiatives (RFAs, contract programs) targeted at making expensive and difficult animal models, such as simian models, more available to the research community studying lung infection.
• Support development of diagnostic and prognostic markers that are tied to or correlated with measures of immune function. Longitudinal correlates with immunity are especially needed where clinical outcomes are unpredictable.
• The National Heart, Lung, and Blood Institute should foster development of innovative approaches including:
  • Systems biology research including mathematical modeling
  • Collaborative efforts to incorporate clinical trial components into basic research (and vice versa)
  • Novel means of non-invasive assessment of disease activity during infection (MRI, CT, etc.)
  • Repeated invasive assessment of disease activity in animal model work

Workshop Organizers and co-chairs:

• Andrew H. Limper, M.D., Mayo Clinic College of Medicine, Rochester, MN, Co-Chair
• Arturo Casadevall, M.D., Ph.D., Yeshiva University, Bronx, NY, Co-Chair

NHLBI Staff:

• Hannah H. Peavy, M.D., Division of Lung Diseases
• Sandra Colombini Hatch, M.D., Division of Lung Diseases
• Dorothy B. Gail, Ph.D., Division of Lung Diseases

Participants:

• Sheila A. Barber, Ph.D. Johns Hopkins University School of Medicine, Baltimore, MD
• Zheng W. Chen, M.D., Ph.D., University Of Illinois at Chicago, Chicago, IL
• Janice E. Clements, Ph.D., Johns Hopkins University School of Medicine, Baltimore, MD
• Beth A. Garvy, PhD, University of Kentucky Chandler Medical School, Lexington, KY
• JoAnne L. Flynn, Ph.D., University of Pittsburgh School of Medicine, Pittsburgh, PA
• Denise Kirschner, Ph.D., The University of Michigan Medical School, Ann Arbor, MI
• Yukari C. Manabe, M.D., Johns Hopkins University School of Medicine, Baltimore , MD
• John Mittler , Ph.D., University of Washington, Seattle, WA
• Karen A. Norris, Ph.D., University of Pittsburgh School of Medicine, Pittsburgh, PA
• Paul R. Skolnik, M.D., Boston University School of Medicine, Boston, MA
• Zahra Toossi , M.D., Case Western Reserve University, Cleveland, OH

December 2005