Reviewing Pathogenesis

Two recent papers review the latest data on the pathogenesis of HIV infection. In the current issue of Nature Medicine, Zvi Grossman and colleagues mull the role of immune activation and emphasize HIV's propensity for replicating in short lived effector T cells. Because such cells are destined to die within 1-2 days due to activation-induced cell death, the initial effects of HIV infection on the T cell immune system are limited, because long-lived naive and central memory T cells - which can give rise to effector T cells upon activation - are relatively spared. Grossman and colleagues argue that recent theories regarding the importance of depletion of CD4 T cells from the gut are likely incorrect because the majority of these cells are short-lived effectors and their depletion can be tolerated. In support of their argument they cite evidence that a similar depletion occurs in SIV-infected Sooty Mangabeys but these monkeys almost never develop immunodeficiency. The review by Grossman et al is partly a response to another review in the March issue of Nature Immunology authored by Jason Brenchley and colleagues from the Vaccine Research Center at NIH. Brenchley et al argue that the early depletion of CD4 T cells from the gut mucosa in HIV infection is a critical insult from which the T cell immune system never recovers. The Brenchley review was published before the data from Sooty Mangabeys emerged. Despite their different perspectives, the authors of both papers would probably agree with the last sentence from Grossman et al:

"Echoing a recent appeal for more fundamental research in the area of HIV vaccine research, we believe that successful interventions depend on achieving basic understanding of the concomitant regulation of immune activation and homeostasis both normally and under conditions of acute and chronic infection."

In other words, the mysteries of HIV pathogenesis will not be fully resolved until the mysteries of the human T cell immune system are revealed and a dedicated research effort is required on that front.

http://www.nature.com/nm/journal/v12/n3/abs/nm1380.html

Nature Medicine, 289 - 295 (2006)
Nature Medicine Published online: 6 March 2006

Pathogenesis of HIV infection: what the virus spares is as important as what it destroys
Zvi Grossman¹, Martin Meier-Schellersheim¹, William E Paul¹ & Louis J Picker³

Upon transmission to a new host, HIV targets CCR5⁺CD4⁺ effector memory T cells, resulting in acute, massive depletion of these cells from mucosal effector sites. This depletion does not initially compromise the regenerative capacity of the immune system because naive and most central memory T cells are spared. Here, we discuss evidence suggesting that frequent activation of these spared cells during the chronic phase of HIV infection supplies mucosal tissues with short-lived CCR5⁺CD4⁺ effector cells that prevent life-threatening infections. This immune activation also facilitates continued viral replication, but infection and killing of target T cells by HIV are selective and the impact on effector-cell lifespan is limited. We propose, however, that persistent activation progressively disrupts the functional organization of the immune system, reducing its regenerative capacity and facilitating viral evolution that leads to loss of the exquisite target cell–sparing selectivity of viral replication, ultimately resulting in AIDS.

¹ Zvi Grossman, Martin Meier-Schellersheim and William E. Paul are in the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

² Zvi Grossman is also in the Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. ³ Louis J. Picker is in the Vaccine and Gene Therapy Institute, and Oregon Regional Primate Research Center, Oregon Health & Science University, Beaverton, Oregon 97006, USA.

http://www.nature.com/ni/journal/v7/n3/abs/ni1316.html

Nature Immunology, 235 - 239 (2006)
Published online: 15 February 2006

HIV disease: fallout from a mucosal catastrophe?
Jason M Brenchley, David A Price & Daniel C Douek

The pathogenesis of human immunodeficiency virus has long been thought to center on a gradual depletion of CD4⁺ T cells, with an average of 100 cells lost per microliter of blood per year. However, studies of macaques infected with simian immunodeficiency virus and humans infected with human immunodeficiency virus have shown that the infection rapidly kills most CD4⁺ T cells at mucosal surfaces. Although most CD4⁺ T cells reside at these sites, the magnitude of this assault on the immune system is not reflected in the peripheral blood. Here we consider models of human immunodeficiency virus disease pathogenesis given those findings and propose a hypothesis to account for particular aspects of the disease during the chronic phase of infection that can be directly attributed to early depletion of mucosal CD4⁺ T cells.

Jason M. Brenchley, David A. Price and Daniel C. Douek are with the Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892 USA.