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Rethinking the AIDS conundrum
CELLULAR
IMMUNOLOGY
144,465-466 (1992)
LETTER TO THE EDITOR Rethinking the AIDS Conundrum To the Editor: The ever-increasing incidence and morbidity of AIDS in the United States and other populations around the globe has stimulated an expanding experimental and clinical research enterprise. The discovery of human immunodeficiency virus type 1 in 1983 provided a focus of attention that dominates laboratory and clinical research and therapeutic efforts. Laboratory investigations center on the molecular mechanisms of virus infection, replication, and cellular pathogenesis. Clinical studies evaluate surrogate markers of infection or loss of cell populations susceptible to HIV- 1 infection for diagnostic purposes. Drugs have been discovered and developed based on their abilities to cope with HIV-l infection principally based on in vitro models of acute virus infection and some have proceeded to clinical trials and approval. These efforts have been directed mainly at understanding the phenomenology of HIV- 1 and toward providing compounds that would block spreading infection in the patient. However, they fail to address directly a crucial aspect of AIDS, namely, that patients succumb to lethal intercurrent infections rather than a direct consequence of HIV-l viremia. The “commensal” agents generally associatedwith intercurrent or “opportunistic” infections are normal elements in our everyday environment. For healthy immunocompetent individuals, encounters with these agents are routine events and pose little or no threat. Unfortunately, the immunologically AIDS-compromised patient is at great risk from these intercurrent infections owing to a critical defect in the natural immunity mechanism that healthy persons depend on for daily protection. As the phylogenetically oldest defense system of vertebrates, the essentiality of phagocytosis for dealing with microbial threats of the environment has been appreciated since the pioneering investigations of Metchnikoff, close to a century ago. The unavoidable, repeated exposure to intercurrent agents suffered by AIDS patients is the most serious and life-threatening situation that they encounter. Considering the role of intercurrent infections in AIDS and the well-characterized mechanisms of host resistance (1) it is surprising that so little attention has been given these important effector cells of natural immunity, and their changes during disease progression. The concept of the mononuclear phagocyte system played a pivotal role in the resurgenceof interest in natural immunity, a noninduced form of host resistance in which macrophages are the ejixtor cells. It is crucial in this regard that recent reports on virus distribution among peripheral blood mononuclear cells demonstrate a predominant infection of CD4+ T cells and infrequent infection of mononuclear phagocytes. Despite repeated observation of HIV- 1-infected macrophages in tissues the general impression persiststhat HIV- 1 infection of macrophagesplays no significant role in AIDS. 465 0008-8749/92 $5.00 Copyright 0 1992 by Academic Press,Inc. All rights of reproduction in any form reserved.
466
LETTER TO THE EDITOR
It may be well to consider that monocyte/macrophage activity in AIDS reflects system-widechangesin immune status of the infected individual (2). Reports on specific phenotypic defects in macrophages from AIDS patients (3) emphasize that these changes can be observed even in the peripheral blood monocyte/macrophages. Accordingly, alterations in monocyte/macrophage effector cell function with the attendant diminution in resistance to intercurrent infection could well be key to the evolving syndrome. Our efforts to develop effective therapies for HIV- 1 infection must be guided by the most basic observations concerning disease progression, its main causes and most prominent mechanisms. Major efforts have been devoted to developing “antiviral” agents, but represent but one possible therapeutic strategy. It is important to confront the realities of HIV- 1 infection and AIDS by encouraging greater efforts to influence the most basic immunological mechanisms that contribute to diseaseprogression. A number of compounds have been developed with the specific intent to promote macrophage effector function. It would be timely and appropriate to consider utilizing certain agentsthat may well “activate” even those “compromised” tissue macrophages presumed to be present but no longer effective in AIDS patients. These such potentially effective products include interferon, endotoxin, and Corynebacteriumparvum cell preparations to name but a few. Careful consideration of the potential for modulating macrophage phenotype as one means of alleviating the sequelae of HIV-l infection may well lead to new concepts and strategies for effective management of AIDS. REFERENCES 1. Fiirster, O., and Landy, M. (Eds.), “Heterogeneity of Mononuclear Phagocytes.Proceedings of an International Workshop, Vienna, July 1980.” Academic Press,London, 1981. 2. Pauza, C. D., Cell. Immunol. 112,414, 1988. 3. Baldwin, G., et al., Proc. Nat/. Acad. Sci. USA 81, 3933, 1990.
MAURICELANDY' 7550 Eads Avenue La Jolla, California 92037
C.DAVID
PAUZA*
Department of Pathology and Laboratory Medicine University of Wisconsin-Madison 1300 University Avenue Madison, Wisconsin 53706 ’ To whom correspondence should be addressed. ’ Supported by PHS Grant AI24591 from the NIAID.
IMMUNOLOGY
144,465-466 (1992)
LETTER TO THE EDITOR Rethinking the AIDS Conundrum To the Editor: The ever-increasing incidence and morbidity of AIDS in the United States and other populations around the globe has stimulated an expanding experimental and clinical research enterprise. The discovery of human immunodeficiency virus type 1 in 1983 provided a focus of attention that dominates laboratory and clinical research and therapeutic efforts. Laboratory investigations center on the molecular mechanisms of virus infection, replication, and cellular pathogenesis. Clinical studies evaluate surrogate markers of infection or loss of cell populations susceptible to HIV- 1 infection for diagnostic purposes. Drugs have been discovered and developed based on their abilities to cope with HIV-l infection principally based on in vitro models of acute virus infection and some have proceeded to clinical trials and approval. These efforts have been directed mainly at understanding the phenomenology of HIV- 1 and toward providing compounds that would block spreading infection in the patient. However, they fail to address directly a crucial aspect of AIDS, namely, that patients succumb to lethal intercurrent infections rather than a direct consequence of HIV-l viremia. The “commensal” agents generally associatedwith intercurrent or “opportunistic” infections are normal elements in our everyday environment. For healthy immunocompetent individuals, encounters with these agents are routine events and pose little or no threat. Unfortunately, the immunologically AIDS-compromised patient is at great risk from these intercurrent infections owing to a critical defect in the natural immunity mechanism that healthy persons depend on for daily protection. As the phylogenetically oldest defense system of vertebrates, the essentiality of phagocytosis for dealing with microbial threats of the environment has been appreciated since the pioneering investigations of Metchnikoff, close to a century ago. The unavoidable, repeated exposure to intercurrent agents suffered by AIDS patients is the most serious and life-threatening situation that they encounter. Considering the role of intercurrent infections in AIDS and the well-characterized mechanisms of host resistance (1) it is surprising that so little attention has been given these important effector cells of natural immunity, and their changes during disease progression. The concept of the mononuclear phagocyte system played a pivotal role in the resurgenceof interest in natural immunity, a noninduced form of host resistance in which macrophages are the ejixtor cells. It is crucial in this regard that recent reports on virus distribution among peripheral blood mononuclear cells demonstrate a predominant infection of CD4+ T cells and infrequent infection of mononuclear phagocytes. Despite repeated observation of HIV- 1-infected macrophages in tissues the general impression persiststhat HIV- 1 infection of macrophagesplays no significant role in AIDS. 465 0008-8749/92 $5.00 Copyright 0 1992 by Academic Press,Inc. All rights of reproduction in any form reserved.
466
LETTER TO THE EDITOR
It may be well to consider that monocyte/macrophage activity in AIDS reflects system-widechangesin immune status of the infected individual (2). Reports on specific phenotypic defects in macrophages from AIDS patients (3) emphasize that these changes can be observed even in the peripheral blood monocyte/macrophages. Accordingly, alterations in monocyte/macrophage effector cell function with the attendant diminution in resistance to intercurrent infection could well be key to the evolving syndrome. Our efforts to develop effective therapies for HIV- 1 infection must be guided by the most basic observations concerning disease progression, its main causes and most prominent mechanisms. Major efforts have been devoted to developing “antiviral” agents, but represent but one possible therapeutic strategy. It is important to confront the realities of HIV- 1 infection and AIDS by encouraging greater efforts to influence the most basic immunological mechanisms that contribute to diseaseprogression. A number of compounds have been developed with the specific intent to promote macrophage effector function. It would be timely and appropriate to consider utilizing certain agentsthat may well “activate” even those “compromised” tissue macrophages presumed to be present but no longer effective in AIDS patients. These such potentially effective products include interferon, endotoxin, and Corynebacteriumparvum cell preparations to name but a few. Careful consideration of the potential for modulating macrophage phenotype as one means of alleviating the sequelae of HIV-l infection may well lead to new concepts and strategies for effective management of AIDS. REFERENCES 1. Fiirster, O., and Landy, M. (Eds.), “Heterogeneity of Mononuclear Phagocytes.Proceedings of an International Workshop, Vienna, July 1980.” Academic Press,London, 1981. 2. Pauza, C. D., Cell. Immunol. 112,414, 1988. 3. Baldwin, G., et al., Proc. Nat/. Acad. Sci. USA 81, 3933, 1990.
MAURICELANDY' 7550 Eads Avenue La Jolla, California 92037
C.DAVID
PAUZA*
Department of Pathology and Laboratory Medicine University of Wisconsin-Madison 1300 University Avenue Madison, Wisconsin 53706 ’ To whom correspondence should be addressed. ’ Supported by PHS Grant AI24591 from the NIAID.