A number of studies have documented that the body’s machinery for producing new immune system cells is impaired by HIV infection. In a new paper in the journal Blood, Delphine Sauce and colleagues delve into the issue further by analyzing circulating CD34+ hematopoietic progenitor cells (HPC) in over one hundred HIV positive individuals at various stages of disease, compared to both age-matched and elderly (75-96 years old) uninfected controls. The research reveals significant correlations between the number of HPC and multiple types of immune cells including CD4 T cells, CD8 T cells, B cells, natural killer cells and neutrophils (the strongest correlation being between circulating HPC and CD4 T cells). The number of HPC is found to decline over the course of HIV disease progression such that middle-aged HIV-positive individuals with CD4 T cell counts less than 200 had similar levels of circulating HPCs to the elderly uninfected controls.
Additional analyses show that markers of immune activation such as CD38 expression on CD8 T cells are inversely associated with HPCs; the higher the levels of immune activation, the lower the HPC counts. The researchers demonstrate that among elite controllers with declining CD4 T cell counts, HPC numbers and functional capacity are diminished despite persistently low viral load, consistent with the link between immune activation and CD4 T cell loss that has been reported in this population. HIV-positive individuals with poor CD4 T cell recovery despite antiretroviral therapy (ART) also show reduced HPC numbers and functional capacity compared to individuals with better immune reconstitution.
The study authors conclude that preservation of lymphocyte production capacity (lymphopoiesis) is important for preventing HIV disease progression and that strategies for enhancing lymphopoiesis should be evaluated in the setting of poor CD4 T cell recovery on ART. One approach that is currently under evaluation in a clinical trial for people on ART with CD4 T cell counts less than 250 is TXA127 (angiotensin 1-7), a drug formulation of a naturally occurring substance that may stimulate production of HPCs.
Published online before print March 24, 2011, doi: 10.1182/blood-2011-01-331306
Blood March 24, 2011 blood-2011-01-331306
Delphine Sauce1, Martin Larsen2, Solene Fastenackels1, Michele Pauchard3, Hocine Ait-Mohand4, Luminita Schneider3, Amelie Guihot1, Faroudy Boufassa5, John Zaunders6, Malika Iguertsira7, Michelle Bailey6, Guy Gorochov2, Claudine Duvivier8, Guislaine Carcelain9, Anthony D Kelleher10, Anne Simon7, Laurence Meyer11, Dominique Costagliola3, Steven G Deeks12, Olivier Lambotte13, Brigitte Autran1, Peter W Hunt12, Christine Katlama3, and Victor Appay1,*
1 INSERM UMR S 945, Infections and Immunity, Avenir Group, Universite Pierre et Marie Curie-Paris6, Hopital Pitie-Salpetriere, Paris, France;
2 Immunoregulation and Immunotherapy, INSERM UMR S 945, Universite Pierre et Marie Curie-Paris6, Hopital Pitie-Salpetriere, Paris, France;
3 INSERM UMR S 943, Universite Pierre et Marie Curie-Paris6, Hopital Pitie-Salpetriere, Paris, France;
4 AP-HP, Groupe hospitalier Pitie-Salpetriere, Service des Maladies Infectieuses et Tropicales, Paris, France;
5 INSERM U81018, University Paris-Sud, Hopital Bicetre, Le Kremlin-Bicetre, France;
6 St Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW, Australia;
7 AP-HP, Groupe hospitalier Pitie-Salpetriere, Service de Medecine Interne, Paris, France;
8 Institut Pasteur, Centre Medical de l'Institut Pasteur; Centre d'Infectiologie Necker-Pasteur, Departement Infection et Epidemiologie, Paris, France;
9 AP-HP, Groupe hospitalier Pitie-Salpetriere, Laboratoire d'Immunologie Cellulaire et Tissulaire, Paris, France;
10 St. Vincent's Centre for Applied Medical Research and University of New South Wales, Sydney, NSW, Australia;
11 AP-HP, Service d'Epidemiologie et de Sante Publique, Hopital Bicetre, Le Kremlin-Bicetre, France;
12 HIV/AIDS Division, Department of Internal Medicine, University of California, San Francisco, San Francisco, CA, United States;
13 AP-HP, Department of Internal Medicine and Infectious Diseases, Hopital Bicetre, Le Kremlin-Bicetre, France
The mechanisms of CD4+ T cell count decline, the hallmark of HIV disease progression, and its relationship to elevated levels of immune activation are not fully understood. Massive depletion of CD4+ T cells occurs during the course of HIV-1 infection, so that maintenance of adequate CD4+ T cell levels likely depends primarily on the capacity to renew depleted lymphocytes, i.e. the lymphopoiesis. We performed here a comprehensive study of quantitative and qualitative attributes of CD34+ hematopoietic progenitor cells directly from the blood of a large set of HIV infected individuals compared with uninfected donors, in particular elderly. Our analyses underline a marked impairment of primary immune resources with the failure to maintain adequate lymphocyte counts. Systemic immune activation emerges as a major correlate of altered lymphopoiesis, which can be partially reversed with prolonged antiretroviral therapy. Importantly, HIV disease progression despite elite control of HIV replication or virological success on antiretroviral treatment is associated with persistent damage to the lymphopoietic system, or exhaustion of lymphopoiesis. These findings highlight the importance of primary hematopoietic resources in HIV pathogenesis and the response to antiretroviral treatments.