Published online before print August 25, 2006
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* The Wistar Institute, Philadelphia, Pennsylvania, USA;
Macfarlane Burnet Institute for Medical Research and Public Health, National Centre for HIV Virology Research, Melborne, Victoria, Australia;
Department of Experimental Medicine and Biochemical Sciences, University of Rome "Tor Vergata," Rome, Italy;
Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA; and
¶ Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA
1 Correspondence: The Wistar Institute, 3601 Spruce St., Philadelphia, PA 19104-4268. E-mail: montaner{at}wistar.org
ABSTRACT
The continued quest to intervene in HIV-1 infection by halting transmission, suppressing replication, or eradicating disease in infected subjects stresses the significance of dendritic cell and macrophage biology as early and persistent players in the relationship between infection and disease. As highlighted by new data and presentations at the Sixth International Workshop on HIV and Cells of Macrophage/Dendritic Lineage and Other Reservoirs, a greater emphasis is currently underway in studying the potential of targeting these cell types by intervention early in infection, better defining viral phenotypes and entry mechanisms with a more precise nomenclature system, identifying new, intrinsic cellular factors that may restrict infection within these cell types, and pursuing novel roles for macrophage activation and trafficking. Other key areas include examination of these cells as sources of viral persistence in patients, their roles in coinfection, and their metabolic function in HIV pathogenesis and drug toxicity. This issue of JLB contains reviews and original research reports from the workshop, which highlight new findings, current research questions, and key areas in need of future investigation as a result of their significance to HIV prevention and pathogenesis.
Key Words: monocyte
INTRODUCTION
Throughout various advances in HIV-1 research during the past 25 years, the predominant role of dendritic cells (DC) and macrophages in HIV disease remains a central piece to infection and pathogenesis, as exemplified by their roles at the initiation of infection, in determining immunological fitness (ability to engage adaptive responses, among others), and mediating viral persistence. This was clearly evident by the research focus, progress, and future directions presented at the sixth meeting of the International Workshop on HIV and Cells of Macrophage/Dendritic Lineage and Other Reservoirs, held in Italy in October 2005, and the subsequent reviews and original research submitted for this issue in 2006. The goals of this issue, like the workshop on which it is based, are to first focus on progress made in understanding the unique molecular, viral, and pathogenesis questions associated with infection of these cell types and second, to identify new opportunities for advancing research based on what we know today.
Emerging from new data and field direction, as presented in this issue, were four broad areas of research activity: 1) HIV-1 infection: distinctions between tropism and entry coreceptor use, the role of DC during mucosal exposure, and the intracellular steps necessary for HIV-1 infection unique to macrophages; 2) better definition of the relevance and cell types that comprise viral reservoirs; 3) modulation of macrophage functions during HIV disease in terms of immune, metabolic, and HIV-related disease outcomes; and 4) preclinical concepts targeting DC or macrophage cellular function of consequence to novel vaccine, therapy, or other antiviral strategies.
DEFINING HIV INFECTION, ENVELOPE-MEDIATED CELLULAR CHANGES, AND TROPISM
Since the discovery of HIV-1 entry coreceptors and their association with infection of different target cells (i.e., T cell lines vs. primary macrophages), target cell tropism and coreceptor selectivity have often been used as interchangeable terms. Now Goodenow (Gainesville, FL) and Collman (Philadelphia, PA) [1 ] address this gap by presenting a new HIV-1 classification system, which highlights the complex relationship between coreceptor selectivity and tropism and the range of combinations among primary isolates. It is interesting that P. Gorry (Melbourne, Australia) characterized CCR5 by R5 HIV isolates, between early and late disease, with a lower requirement for CCR5 and higher replication in late isolates (oral presentation).
Following interactions with CD4 and coreceptor molecules, great advances have been made within the last three years as reviewed by Wahl (Bethesda, MD) et al. [2
] in identifying macrophage- versus T cell-specific steps, which may determine infection efficiency. These include additional cell membrane interactions and intrinsic cellular factors that modulate infection and/or viral replication in a cell-specific manner, specifically, recently identified binding factors needed for macrophage infection following viral binding and infection such as annexin-II and p21, respectively. A role for 
-v integrin to intervene in macrophage infection was also presented by Bosch (Barcelona, Spain) et al. (published this year; ref. [3
]), based on effects of blocking this molecule before infection. Lastly, novel inner-nuclear envelope proteins were described to be required for HIV infection in macrophages by Stevenson (Worcester, MA) and colleague (published this year; ref. [4
]) with a dependent role for emerin and barrier-to-autointegration factor (BAF) nuclear envelope proteins in HIV infection. The area of macrophage infection and the likelihood that more cellular factors are needed in the regulation of infection, integration, and viral release make this area a current focus of much research activity.
General immune activation following viral infection is associated with type-I IFN production as a host antiviral response. Hosmalin (Paris, France) and colleague [5
] now review this response within HIV pathogenesis, addressing the observations that a DC able to secrete type-I IFN is also associated with delayed disease progression. Of interest to IFN- antiviral effects in macrophages, Wahl (Bethesda, MD) and co-workers (published this year; ref. [6
]) reviewed data about the mechanism of IFN--mediated resistance of macrophage infection via regulation of APOBEC3. Chougnet (Cincinnati, OH) and Gessani (Rome, Italy) [7
] present a closer examination of the relationship between DC dysfunction as an outcome of viral envelope interactions. It is interesting that viral replication and the predominance of noninfectious particles in vivo are stressed as having a dominant effect on DC biology by way of viral envelope interactions alone. Cunningham (Sydney, Australia) and co-workers [8
] address the multiple aspects of DC biology affected by HIV infection at entry and throughout pathogenesis and stresses the few tissue-based studies available to more fully understand the role of these cells at the onset and throughout disease.
MACROPHAGES AS HIV RESERVOIRS
The study of macrophages as viral reservoirs or "Trojan horse" in lentiviral infections is not new. In the context of HIV-1 infection is intensified further by the long-standing observation that HIV-1 infection of macrophages is not associated with cytopathic effects as with T cell infection and is preferentially produced within intracellular vesicles. Poli (Milan, Italy) and co-workers [9 ] present a review about the study of macrophages and monocyte cell lines as HIV-1 targets for viral infection to stress the benefits and limitations of each system. M. Marsh (London, UK) presented the role of the endocytic compartment in facilitating HIV assembly and avoidance of humoral responses (oral presentation). New data about viral particle production within macrophage "viral endosomes" with expression of CD81, CD9, and smaller amounts of CD63 and MHC-II were associated with an increased infectivity.
Studies of the role for macrophages in contributing to chronic viral populations in vivo have been largely restricted to specific organ systems (i.e., lung, CNS) or end-stage disease when CD4 T cells are limiting. There is an increasing focus on examining macrophage viral production throughout disease as presented by Zhu (Seattle, WA) and colleagues [10 ], who shows new data about distinct evolution of HIV-1 sequences in monocytes in vivo even after viral suppression following antiretroviral therapy. Although data about macrophage cell reservoirs are still beyond our ability to measure directly in vivo, Cara (Rome, Italy) and Klotman (New York, NY) [11 ] review data about integrated versus extrachromosmal proviral DNA and their persistence in nondividing cells, and Brown (Baltimore, MD) et al. [12 ] present data about research intended to explore persistence in vitro. Further defining the presence and decay rate of latent versus active macrophage HIV infection within tissues remains an important but largely unexplored area.
IMPACT OF MACROPHAGE ACTIVATION AND FUNCTION IN HIV PATHOGENESIS
Macrophage activation and function in HIV infection have been areas of continuous study from the beginning of the HIV research effort as a result of the presence of this cell subset in every organ system and its chronic activation state throughout disease. Several reviews and research presented here address advances in this large yet understudied area, such as Montaner (Philadelphia, PA) and co-workers [13 ] reviewing gene expression profiling of HIV target cells (i.e., T cells, macrophages) in vitro/in vivo, highlighting new findings from 2000 to 2006. Smith (Birmingham, AL) and colleagues [14 ] present new, important data about the ability of CMV to induce viral infection and replication with intestinal macrophage populations, a macrophage population previously understood to be refractory to HIV.
The interactions between tissue microenvironment and coinfection were addressed by Wahl (Bethesda, MD) and co-workers [15 ], reporting factors associated with tonsil tissue infection as well as the presence of suppressor of cytokine signaling-mediated suppression of macrophage function following infection with Mycobacterium avium complex [16 ]. Gabuzda (Boston, MA) and colleagues [17 ] addressed the interactions between activated monocytes and endothelial cells as a potential insight into HIV-associated tissue damage, such as in the CNS. Bukrinsky (Washington, DC) and Sviridov (Melbourne, Australia) [18 ] review a new area in macrophage cholesterol metabolism with regard to activation stressing the potential role for this function in viral replication and endothelial damage leading to atherosclerotic lesions. Crowe (Melbourne, Australia) and colleague [19 ] reviewed a new focus on matrix metalloproteinases as a product of activated macrophages in classifying the potential role for these molecules in disease such as HIV-associated dementia. Neuronal damage and macrophage activation are reviewed by Gras (Fontenay-aux Roses, France) et al. [20 ] centering on the glutamate-glutamine cycle and its potential for segregating damaging and protective roles for activated microglia and macrophages within the CNS. Taken together, manuscripts addressing macrophage activation and function stress the increasing direction of new research into new target areas to better define the connection between macrophage function and the various pathology outcomes observed in HIV disease.
CLINICAL INTERVENTIONS ADDRESSING DC FUNCTION, THERAPY DELIVERY, AND MACROPHAGE RESERVOIRS
Apart from an effective vaccine, among the most promising clinical interventions planned is the implementation of an effective barrier to mucosal transmission via microbicides, as reviewed by Robbiani (New York, NY) and co-workers [21 ]. Weissman (University of Pennsylvania, Philadelphia) also described novel research about cystine-rich scavenger receptor gp-340 as a novel binding protein for HIV ("cell surface sink for virus") (oral presentation). gp-340 was stressed for relevance to vaginal infection as a result of its expression within vaginal epithelial cells and potential use in prevention strategies. D. Schols (Leuven, Belgium) presented use of sugar-binding proteins to inhibit HIV-1 infection with several compounds highlighted for a high antiviral activity without lymphocyte activation activity (oral presentation).
Kornbluth (San Diego, CA) and colleague [22 ] reviewed manipulation of immune responses via adjuvants for the development of HIV-1 vaccines, stressing the targeting of DC activation as a general goal for most adjuvants in development today. Perno (Rome, Italy), Aquaro (Rende, Italy), and co-workers [23 ] addressed suppression of macrophage HIV-1 replication during chronic infection by reviewing the unique aspects in macrophage infection of antiretroviral agents currently available and in development. Novel therapeutic strategies were discussed by Berger (Frederick, MD) and co-workers [24 ], who presented preclinical data about targeted immunotoxins as an approach to eradicate infected reservoir cells in vivo, and Gendelman (Omaha, NE) and colleagues [25 ], who presented data about an approach that exploits the tissue-trafficking properties of monocytes to use them as drug delivery agents for antiretroviral therapy.
CONCLUSIONS
Novel data and areas presented at the workshop and this issue centered on stressing new, early viral intervention strategies, exploiting new targets, inhibiting viral binding such as sugar-binding proteins, gp-340, and annexin-II in combination with coreceptor blockers within microbicides; identification of novel determinants of macrophage infection such as nuclear envelope proteins (emerin/BAF), p21, and immune regulation of APOBEC3 by type-1 IFNs; defining a better classification to define tropism versus coreceptor use; defining new, target mechanisms of macrophage and DC dysfunction and biology in HIV pathogenesis; and new antiviral strategies such as drug-loading of monocyte and tissue trafficking or immunotoxins.
Based on the advances today, where will research progress take us 3–5 years from now? It is clear that the research summarized here outlines several novel targets for intervention within the cascade of host factors needed for infection and/or macrophage/DC functions in association with disease outcomes. Therefore, it remains as important today, as ever, to formally document our collective progress/research gaps if we are to facilitate future advances toward better strategies against prevention and eradication.
ACKNOWLEDGEMENTS
The organizers thank the sponsors of the Sixth International Workshop on HIV and Cells of Macrophage/Dendritic Lineage and Other Reservoirs: The Office of AIDS Research, National Institutes of Health (Bethesda, MD); The National Centre for HIV Virology Research (Australia); and the Istituto Superiore di Sanità (Italy).
Received August 1, 2006; revised August 2, 2006; accepted August 6, 2006.
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