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Immunopathogenic Mechanisms of HIV Infection FREE

Anthony S. Fauci, MD; Giuseppe Pantaleo, MD; Sharilyn Stanley, MD; and Drew Weissman, MD, PhD
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A summary of a conference held on 29 June 1994 at the Clinical Center of the National Institutes of Health, Bethesda, Maryland. Moderator: Anthony S. Fauci; Discussants: Giuseppe Pantaleo, Sharilyn Stanley, and Drew Weissman Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference Pantaleo G. Virologic and immunologic events associated with primary HIV infection, pp. 655-7. In: Fauci AS, moderator. Immunopathogenic mechanisms of HIV infection. Ann Intern Med. 1996:124:654-63. Requests for Reprints: Anthony S. Fauci, MD, Building 10, Room 11B13, 10 Center Drive MSC 1876, Bethesda, MD 20892-1876. Current Author Addresses: Drs. Fauci and Stanley: Building 31, Room 7A03, 31 Center Drive MSC 2520, Bethesda, MD 20892-2520.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1996;124(7):654-663. doi:10.7326/0003-4819-124-7-199604010-00006
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A complex array of multiphasic and multifactorial immunopathogenic mechanisms are involved in the establishment and progression of human immunodeficiency virus (HIV) disease.After primary infection, acute viremia occurs with wide dissemination of HIV. During this early viremic phase, the virus is trapped within the processes of follicular dendritic cells in the germinal centers of lymphoid tissue. Also, during this phase of primary infection, some patients show major expansions of certain subsets of CD8+ T cells that are identified by the expression of a particular variable region of the β chain of the T-cell receptor. These expansions are manifestations of responses to HIV that may be important in controlling the progression of HIV infection. In addition, inappropriate immune activation and elevated secretion of certain proinflammatory cytokines occur during HIV infection; these cytokines play a role in the regulation of HIV expression in the tissues. Infection of progenitor cells in bone marrow and the thymus contribute to the lack of regeneration of immunocompetent cells. Dendritic cells are involved in the initiation and propagation of HIV infection in CD4+ T cells. In studies of long-term nonprogressors—persons who have stable CD4+ T-cell counts and no HIV disease progression despite years of HIV infection—preserved lymph node architecture, low viral burden, and viral expression were found.

Dr. Anthony S. Fauci (National Institutes of Health [NIH], Bethesda, Maryland): The immunopathogenic mechanisms of infection with the human immunodeficiency virus (HIV) are multifaceted and multiphasic [1]. Figure 1 shows the typical prolonged course of HIV disease. The complex nature of HIV disease involves various overlapping features, including persistence of viral replication, aberrant and persistent immune activation, cytokine secretion and dysregulation, and, ultimately, progressive immunologic deterioration [12].

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Figure 1.
Typical course of human immunodeficiency virus (HIV) infection.The New England Journal of Medicine

The complex, multifactorial, multiphasic, and overlapping factors of the immunopathogenic mechanisms of HIV disease are shown. Throughout the course of HIV infection, virus replicates and immunodeficiency progresses steadily, despite the absence of observed disease during the so-called clinical latency period. Immune activation and cytokine secretion vary among HIV-infected persons, sometimes increasing dramatically as disease progresses. Immune activation and cytokine secretion play a major role in pathogenesis. Adapted from reference 2 by permission of . Pantaleo et al. 1993; 328:327-35.

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Soon after HIV enters the body, it is widely disseminated, predominantly to lymphoid tissues [14]. The burst of virus replication early in the course of HIV disease is partially, but not completely, contained by an appropriate immune response [57], together with trapping of virions in the lymphoid tissue (see below). The onset of a robust immune response leads to a marked downregulation of virus in the blood [78]. However, with rare exceptions, virus is not completely eliminated from the body, and a state of chronic, persistent viral replication ensues. In almost all other viral infections of humans, virus either kills the host within a short period (this is relatively rare), is completely eliminated from the body (this is the case with most viral infections), or enters a state of microbiological latency (this often occurs with herpes simplex virus infections). This transition by HIV from acute to chronic infection with persistent replication of virus (see below) is unique among viral infections in humans.

We have previously shown that the lymphoid tissue is the major reservoir for and site of persistent viral replication; this is true even early in the course of infection, during the period of clinical latency when the CD4+ T cell count is only moderately decreased [3]. With the availability of sensitive assays for plasma viremia, it became clear that plasma viremia could also be measured at every stage of HIV infection, including the early asymptomatic stage [9]. Most recently, it has been shown [1011] that virus is present at high levels in the plasma and rapidly turns over, particularly in advanced-stage disease. In this setting of persistent viral replication, progressive deterioration of immune function usually occurs, ultimately resulting in profound immunosuppression and clinically apparent disease [3, 56]. The link between the persistent replication of HIV and chronic activation of the immune system is critical to the pathogenic events seen in HIV disease [1, 1213].

In the early stage of HIV infection, the lymph nodes of persons with progressing HIV disease are activated and hyperplastic, and many virions are trapped in the germinal centers of lymph nodes in an extracellular manner on follicular dendritic cells [34]. This occurs when production of virus by individual cells within lymphoid tissue is low [3, 1415]. Virus continues to be trapped by follicular dendritic cells in the germinal centers of the lymph nodes, initiating continuous immune stimulation [16] and constant exposure to possible infection of CD4+ T cells that reside in or are migrating through the lymph nodes [12, 16]. In this regard, recent studies [1718] have shown that the HIV that is trapped on the follicular dendritic cells is infectious for CD4+ T cells, even though the virions are coated with neutralizing antibodies. Thus, the mechanisms operable in an appropriate immune response to HIV, particularly activation of the immune system, are paradoxically the same mechanisms that propagate HIV infection and lead to the ultimate destruction of lymphoid tissue and to profound immunosuppression [1].

Cytokine secretion is closely linked with the phenomenon of generalized cellular activation. Since the mid-1980s, our laboratory has studied the role of cytokines in the pathogenesis of HIV disease [19]. Cells communicate with each other through the secretion of cytokines as part of normal immunoregulatory homeostatic mechanisms [20]. During HIV infection, cytokines are hyperexpressed and, in some cases, dysregulated. Constitutive expression of cytokines was examined in the HIV-infected lymph node, where virus-infected cells reside, to determine their potential physiologic relevance. The constitutive and induced expression of various cytokines was assayed by polymerase chain reaction (PCR) [21]. At early, intermediate, or advanced stages of disease, it was found that interleukin-6, tumor necrosis factor-α, interferon-γ, and interleukin-10 were over-expressed in the lymph nodes of HIV-infected persons compared with the lymph nodes of persons with other diseases. In contrast, interleukin-2 and interleukin-4 were rarely secreted constitutively at any stage of HIV disease, despite a state of persistent immune activation.

Previous studies of chronically infected monocyte and T-cell lines [2224] showed that cytokines such as interleukin-1 β, interleukin-6, granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor-α can upregulate HIV expression. These observations assume potential physiologic relevance in light of the fact that several proinflammatory cytokines capable of inducing HIV expression are chronically overexpressed in the lymphoid tissue of HIV-infected persons [21]. We have recently shown that a tightly controlled autocrine loop of endogenous cytokine control of HIV expression exists [25]. In this regard, inhibitors of cytokine expression can markedly downregulate the expression of HIV in an in vitro infection model. Hence, the expression of HIV in vivo is probably at least partly modulated by the endogenous cytokine network that is generally responsible for maintaining the homeostasis of the immune system.

Dr. Giuseppe Pantaleo (NIH): A substantial proportion (50% to 70%) of persons with primary HIV infection have a clinical syndrome of variable severity [56, 8]. The symptoms associated with this syndrome are nonspecific and may include fever, sore throat, skin rash, lymphadenopathy, splenomegaly, myalgia, arthritis, and, less often, meningitis. The lack of specificity and the variable severity of the clinical syndrome may explain, at least in part, why most HIV-infected persons generally do not report the symptoms of primary HIV infection to the physician.

However, delineation of the immunologic and virologic events associated with primary infection is important for several reasons. First, infection is established and virus is systemically disseminated during primary HIV infection. Second, during this period, the initial encounter between HIV and the immune system of the host occurs, and an HIV-specific immune response is generated. Third, although both cellular and humoral immune responses are detected early in primary infection, these HIV-specific immune responses fail to eliminate HIV completely (see above). This suggests that the immune response may be inadequate or that certain mechanisms of viral escape from the immune response may be operative.

Cell-mediated and humoral immune responses specific to HIV have been detected early in primary HIV infection [57, 2627]. The contribution of these immune responses to the dramatic downregulation of viral replication during primary infection has been debated. It is likely that both cell-mediated and humoral immune responses are important in the initial downregulation of HIV replication. The cell-mediated immune response consists predominantly of HIV-specific cytotoxic T lymphocytes and is critical in the elimination of virus-expressing cells; thus, it results in decreased virus production [26, 28]. The humoral immune response, composed of antibodies against different HIV proteins, may substantially contribute to the downregulation of viremia through the formation of immune complexes composed of virus particles, immunoglobulin, and complement (C prime) that may be trapped in the reticulo-endothelial system [16, 28]. The appearance of trapped virus in the follicular dendritic cell network of germinal centers in lymph nodes coincides with an increase in the levels of C prime binding antibodies. In contrast, neutralizing antibodies are detected only several months after seroconversion. Therefore, the downregulation of viremia during the transition from the acute to the chronic phase of HIV infection may result from the combined action of both cellular and humoral immune responses.

To better characterize the cell-mediated immune response during primary HIV infection, we analyzed the T-cell receptor repertoire in peripheral blood mononuclear cells [27]. Both CD4+ and CD8+ T cells can be further subdivided on the basis of “families” of cells that are identified by a particular variable region of the β chain of the T-cell receptor (V β). The entire spectrum of V β families, which number 24, are referred to as the “V β repertoire” of T cells. The V β repertoire has been analyzed on peripheral blood mononuclear cell samples collected at different time points after the onset of symptoms by combining a semiquantitative polymerase chain reaction (PCR) assay and cytofluorometry. The analysis, done in 20 persons with primary HIV infection, showed three predominant patterns of perturbations of the V β repertoire: major expansion in a single V β, moderate expansions in more than one V β, and no expansions or minimal expansions in one or more V β families.

We then determined the cell subset involved in these expansions and the antigen specificity and function of the expanded V β cell subsets. Patient 1, who is representative of the group that showed a major expansion in a single V β family, has been an ideal patient in whom to address these issues. Results from analyses of Patient 1 are shown in Figure 2. Peripheral blood mononuclear cell samples were collected at different time points (days 16, 20, 34, and 136 after the onset of symptoms), and the V β repertoire was analyzed by using semiquantitative PCR. This analysis showed high expression of one V β family, V β 19 (corresponding to V β 17 in the new nomenclature). Sixteen days after the onset of symptoms, V β 19 represented about 40% of the total circulating T lymphocytes, whereas all other V β families were expressed at low levels (Figure 2). The percentage of V β 19 progressively decreased over time (4% at day 136; Figure 2). The results obtained by PCR were confirmed by cytofluorometry in which an antibody against V β 19 was used (data not shown).

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Figure 2.
Perturbation of T-cell subsets during primary human immunodeficiency virus (HIV) infection: patient 1.

Analysis of the T-cell antigen receptor repertoire during primary HIV infection by a semiquantitative polymerase chain reaction assay showing a transient but marked increase in the number of circulating Vβ19+ cells acutely after HIV infection. Adapted from reference 27 by permission of Nature. 1994; 270:463-7.

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The cell subsets involved in these expansions were determined by using two-color cytofluorometry of V β 19 compared with CD4 and CD8 antigens. The number of CD4+ T lymphocytes remained unchanged over time, whereas the expansion of Vβ19+ cells was shown to be predominantly within CD8+ T cells (data not shown). Furthermore, cytofluorometry showed that 20 days after the onset of symptoms, about two thirds of all CD8+ T cells were activated as indicated by the expression of HLA-DR antigen; more than 75% of these activated CD8+ T cells belonged to the Vβ19+ cell subset. This suggests that these cells could potentially be involved in an antigen-specific immune response against HIV (data not shown). This hypothesis was further supported by the finding that the kinetics of V β 19 expansion coincided with those of viral replication during primary HIV infection. Sequence analysis of several recombinant clones of V β 19 obtained from peripheral blood mononuclear cells showed that the expansion of CD8+ T cells was oligoclonal in nature. This further indicated that these expanded CD8+ Vβ19+ cell subsets contained precursors of HIV-specific cytotoxic T lymphocytes and that these expansions were probably driven by HIV.

These expansions of V β subsets may have clinical and biological significance. Preliminary data indicate that different patterns of V β expansions are associated with different clinical outcomes: Major expansions in a single V β are associated with rapid clinical progression, whereas moderate, minimal, or absent V β expansions are associated with a stable and more favorable clinical outcome. This pattern of immune response is probably not unique to HIV infection but may be generated in various viral infections and may not have been recognized previously because of the limited availability of biological specimens collected during the acute phase of viral infections. Elucidation of the biological significance of this type of immune response may provide important insights into the protective as well as the potentially pathogenic mechanisms involved in the immune response to HIV.

Dr. Sharilyn Stanley (NIH): A striking feature of HIV infection is the typically persistent decline in the peripheral blood CD4+ T lymphocyte count throughout the course of HIV disease [1, 20]. Although numerous factors undoubtedly contribute to this loss, the lack of ability to completely regenerate or repopulate these cells may be due to a failure of the bone marrow, the thymic progenitor cells, or the thymic and lymphoid tissue stromal environment that is critical in the generation of immunocompetent cells. In this regard, HIV-infected persons have a high incidence of cytopenias and other hematologic abnormalities [29], and hematopoiesis has been shown to be depressed. It has been shown that CD34+ bone marrow cells, a population of cells that includes both the pluripotent stem cell and the committed myeloid progenitor cell, can be infected with HIV in vitro [30].

To address the question of in vivo progenitor-cell involvement in HIV infection, CD34+ cells that had been enriched to 99% purity from the bone marrow of HIV-infected Zairian and American patients were examined for the presence of culturable HIV or HIV that could be detected by DNA PCR. In each group of patients, a subset of persons was found to have HIV infection in this purified CD34+ progenitor-cell fraction to a level that could not be explained by the approximately 1% contamination with other cells [31]. In certain patients, HIV could be isolated more efficiently and to a higher titer from CD34+ bone marrow cells in vitro than from the remaining CD34 bone marrow cells; viral burden, as measured by quantitative DNA PCR, was higher in the progenitor-cell population in these patients than in the CD34-depleted bone marrow mononuclear cells. In the Zairian patients, no correlation among stage of disease, hematologic variables, and infection of progenitor cells could be established because of numerous confounding factors such as malaria and sickle cell anemia. However, among the U.S. patients, only persons with markedly reduced total CD4+ T-cell counts (< 50 cells/mu L) had infection in the progenitor-cell population, suggesting that infection of these cells is a late event in these patients.

Thus, it is clear that bone marrow progenitor cells identified by the presence of the CD34 antigen on their surfaces can be infected with HIV in vitro and are infected with HIV in vivo in a subset of persons. Although in vitro infection of these cells is ultimately cytopathic, the fate of the cells infected in vivo, including their hematopoietic capacity and their ability to serve as a reservoir for chronic virus production in the bone marrow, are unknown. Furthermore, the contribution of this in vivo infection to the clinically observed hematologic abnormalities is unclear. It seems likely that several factors, such as abnormal cytokine production in the bone marrow and infection of stromal or other bone marrow cells, contribute to the overall hematologic defects in various persons; infection of bone marrow progenitor cells may play an important role only in late-stage disease, when patients often develop varying degrees of pancytopenia.

In addition to the bone marrow abnormalities observed in these persons, several studies have shown marked abnormalities in the thymuses of HIV-infected adults, children, and neonates [32]. These abnormalities typically include thymocyte depletion, premature atrophy of the thymus, and disruption of the thymic stromal network. Because it is difficult to obtain thymic tissue from patients, most of these studies have been done on autopsy material. To study in greater depth the role of the thymus in HIV infection, a model of human thymopoiesis, the severe combined immunodeficient (SCID)-hu mouse, was used. This model consists of a SCID mouse into which specimens of human fetal thymic tissue (providing the stroma) and liver tissue (providing the progenitor cells that seed the stroma) are implanted under the renal capsule, which holds the tissues in close proximity [33]. These tissues vascularize and grow over 2 to 3 months into a human thymus with normal appearance Figure 3 A.

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Figure 3.
Infection of the SCID-hu thymus with human immunodeficiency virus (HIV).

Human fetal thymus and liver are implanted under the renal capsule of the SCID (severe combined immunodeficient) mouse and allowed to mature over 3 to 4 months (original magnification × 15). A. Uninfected, normalappearing thymus with distinct lobes, well-defined corticomedullary junctions, and Hassall corpuscles. B. HIV-infected thymus. A primary isolate of HIV was injected intrathymically, and the tissue was harvested 3 weeks later. Note the marked thymocyte depletion, fibrosis, and infiltration with adipose tissue (original magnification × 15). C. Electron microscopic image of HIV-infected thymus showed marked dropout of thymocytes, leaving behind the network of interdigitating thymic epithelial cells (original magnification × 2300). D. Destruction of thymic epithelial cells. The thymocytes in this area of an HIV-infected thymus appear healthy, but the thymic epithelial cells are degenerating, appearing to undergo a toxic insult with resultant cell death. No HIV is visible (original magnification × 6000).

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Using the SCID-hu model, we and others [3436] have shown that this tissue can be infected with HIV. Injection of virus into the thymic tissue resulted in a spreading cytopathic infection, depletion of thymocytes, and disruption of the thymic stromal network Figure 3 B. In situ hybridization for HIV RNA showed diffuse signals throughout the thymus, indicating the presence of many infected cells in both cortex and medulla, and electron microscopy showed that most of these infected cells were thymocytes that were extremely permissive for infection; multiple virions were often seen budding from a single cell (data not shown). By using DNA and RNA PCR analysis of thymocytes that had been teased from the tissues and sorted into CD4-CD8 double-positive and CD4 or CD8 single-positive populations, it was shown [34] that all populations of cells are infected with HIV; the kinetics of infection differed between the different cell types. CD4+ cells were infected first, followed by CD8+ and CD4+CD8+ thymocytes [34].

Infection of thymocytes was cytopathic; this is shown most impressively by electron microscopic images of areas of thymus in which lacunae were created by the dropout of thymocytes, leaving the interconnected network of thymic epithelial cell processes Figure 3 C. Perhaps more importantly, the thymic stromal environment was severely disrupted as a result of this infection. As shown in Figure 3 D, certain areas of the thymus showed intact thymocytes but degenerating thymic epithelial cells and loss of the critical intimate contact between the thymocytes and thymic epithelial cells. By combining HIV in situ hybridization with immunohistochemical stains for antigens specific for thymic epithelial cells, productive infection of these thymic epithelial cells with HIV could be shown (data not shown).

In summary, HIV infects not only mature CD4+ T cells but also bone marrow progenitor cells, developing thymocytes, and thymic stromal cells, associated with marked disruption of the thymic microenvironment. The importance of these findings lies principally in their implications for immune reconstitution. Although antiretroviral therapy is a cornerstone of treatment for HIV-infected persons, it has become increasingly apparent that therapeutic strategies targeted to the regeneration of a normal immune system are also needed. It is currently not known whether lymphoid tissues, such as the thymus or lymph node, can regenerate after viral replication has been adequately controlled, but maintaining or restoring an intact thymic and lymphoid stromal microenvironment will clearly be vital to the reconstitution of the immune system in HIV-infected persons.

Dr. Drew Weissman (NIH): Dendritic cells are a population of extremely potent antigen-presenting cells derived from the bone marrow and present in almost every tissue in the body; these cells are vital in the initiation of T-cell responses, particularly responses to new antigens [37]. Dendritic cells function by taking up antigens and processing them into peptides that are associated with surface major histocompatibility complex proteins, the complex that interacts with the lymphocyte antigen receptor. The cells then migrate to lymphoid organs and activate T cells in the paracortical regions by presenting the major histocompatibility complex-bound antigen to the T cells. The role of dendritic cells in HIV disease is controversial. In certain studies [3840], these cells have been found to be dysfunctional, depleted, infected in vivo, and susceptible to infection in vitro; findings from other studies contradict these results [4142]. Additionally, HIV-pulsed dendritic cells have been found to infect activated CD4+ T cells [43], and conjugates of dendritic cells and T cells have been isolated from skin sections and found to be easily infected with HIV in vitro [44]. We believe that the contradictory findings about dendritic cell infection, dysfunction, and depletion can be explained by the existence of three populations of cells with dendritic morphology that are present in peripheral blood; only one of these populations is susceptible to infection with HIV in vitro.

To show this, dendritic cells were isolated from peripheral blood by culturing peripheral blood mononuclear cells in vitro and successively depleting T, B, natural killer, and monocytic cells until a morphologically pure population of cells with dendritic structure was obtained [3842]. Similar methods were used to isolate precursors of dendritic cells, except that no in vitro culturing step was used before purification [4546]. These precursors develop into dendritic cells when allowed to mature in culture. Mature dendritic cells purified by standard techniques, including in vitro culture, were analyzed for expression of CD83, an antigen previously shown to be present on dendritic cells in peripheral blood [47], HLA-DR, CD32 (receptor for the Fc region of the IgG molecule [Fc γ R] type II), and CD64 (Fc γ R type I). Two populations of cells were identified, one that was strongly positive for HLA-DR and CD83, and a second, expressing lower HLA-DR levels, that was negative for CD83 and had low Fc γ R I and II levels [48]. Under light and electron microscopy, these two populations of cells showed similar dendritic structures (Figure 4). The function of these two populations of cells was tested in an autologous mixed lymphocyte reaction that measured the ability of antigen-presenting cells to activate autologous T cells. The CD83-positive cells gave substantial stimulation (as much as a 10-fold increase over control conditions), whereas the CD83-negative-FcR-positive cells stimulated only slightly (less than a two-fold increase over control conditions) [48]; this was similar to the degree of stimulation provided by macrophages.

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Figure 4.
Analysis of dendritic cells from human peripheral blood.[38-41]

Dendritic cells purified from peripheral blood by standard methods showed two populations with similar structure. Dendritic cells were isolated from peripheral blood mononuclear cells by density gradient centrifugation through 12.5% (weight/volume) metrizamide (Sigma, St. Louis, Missouri). The low-density cells were shown to be depleted of T, B, natural killer, and monocytic cells by specific staining with monoclonal antibodies and flow cytometry. A. Light microscopy showed that more than 90% of the cells had lobulated nuclei and multiple long cytoplasmic extensions (veils) (original magnification × 400). B. Transmission electron microscopy showed cells with long veiled processes, extensive Golgi regions, and lobulated nuclei. The individual cells shown in panels A and B morphologically represent the entire population (original magnification × 5500).

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Dendritic cell precursors isolated by standard methods without in vitro culture [4546] were found to be negative for CD83 but, when allowed to mature in culture, gained CD83 positivity as well as the immunostimulatory properties and morphologic appearance of mature dendritic cells [48]. In addition to the CD83-negative dendritic-cell precursors that developed into CD83-positive dendritic cells in culture, CD83-positive dendritic cells were isolated directly from peripheral blood mononuclear cells with no in vitro culture using positive selection with CD83- or HLA-DR-specific antibodies. When these two populations of dendritic cells were analyzed in an autologous mixed lymphocyte reaction, dendritic cells derived from precursors were less potent stimulators than were mature dendritic cells isolated directly from peripheral blood mononuclear cells. This suggests that the accumulation of antigens in vivo gave the mature dendritic cells isolated directly from peripheral blood mononuclear cells a superior ability to stimulate autologous CD4+ T cells [48].

Thus, three populations of cells with either dendritic structure or the ability to develop dendritic structure are present in peripheral blood. Two populations appear to be similar cells at different stages of maturation, whereas the CD83-negative-Fc γ R-positive cells have the same structure as dendritic cells but are functionally more similar to monocytes. All three populations express CD4 at low levels, although the CD83-positive cells and dendritic-cell precursors lose CD4 expression in culture [48]. On exposure to HIV, only the Fc γ R-positive cells become infected as measured by released reverse transcriptase activity or DNA PCR analysis for HIV gag DNA [48].

The CD83-positive mature and precursor dendritic cells were not susceptible to HIV infection, but they still appear to play an important role in HIV pathogenesis. When these CD83-positive dendritic cells were pulsed with HIV, extensively washed, and then viewed using transmission electron microscopy, numerous virions were found attached to the cell surfaces. If the cells were left in culture for 24 hours after virus pulsing before examination with transmission electron microscopy, virions were still present on the surface [49]. The HIV-pulsed dendritic cells, when added to unstimulated, autologous CD4+ T cells, could induce infection of the T cells (Figure 5). Dendritic cells, whether pulsed with a low multiplicity of HIV infection (0.0001) (Figure 5, top) or added in small numbers (1 HIV-pulsed dendritic cell per 180 CD4+ T cells; Figure 5, bottom), could still induce a productive infection in CD4+ T cells in the absence of exogenous stimuli. B cells and monocytes pulsed with HIV could not infect autologous CD4+ T cells (Figure 5).

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Figure 5.
Human immunodeficiency virus (HIV)-pulsed CD83+ dendritic cells can bind virus to their surfaces and transmit virus to unstimulated, autologous CD4+ T cells.IIIB6Top.closed circleBottom.IIIB6

The CD83+ population of cells with dendritic structure were purified by flow cytometry using HLA-DR brightness. Monocytes were purified by adherence to plastic for 24 hours. B cells and CD4+T cells were isolated with CD19 and CD4 magnetic beads (Dynal, Lake Success, New York) and were detached from the beads as per the manufacturer's instructions. Cells were pulsed with HIV at various concentrations for 1.5 hours at 37 °C and then washed three times. The HIV-pulsed cells were added to CD4+T cells (2 × 10 /well) and followed for released reverse transcriptase activity. CD4+ T cells and HIV-pulsed cells were mixed at a ratio of 1:10 and were followed for infection. Dendritic cells were pulsed with HIV at a multiplicity of infection of 0.01 □, 0.001 (open diamond), and 0.0001 ○. Monocytes (▵) and B cells ( ) were pulsed with HIV at a multiplicity of infection of 0.01. Cells were pulsed with HIV at an multiplicity of infection of 0.01 and were added in decreasing numbers to 2 × 10 CD4+ T cells. Peak reverse transcriptase activity of the infection is shown. RT CPM = referse transcriptase counts per minute.

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One function of dendritic cells is to migrate through the body, bind and process antigens, and activate T cells. It has recently been shown [50] that dendritic cells are the first cells to appear at sites of inflammation in mucous membranes. Given these findings, a model of the initiation of HIV infection is that HIV enters through a defect or site of inflammation in a mucous membrane and is bound by dendritic or Langerhans cells. Dendritic cells then carry HIV to a lymphoid organ and migrate to the paracortical region, which is rich in CD4+ T cells. These CD4+ T cells are activated by the dendritic cells and are exposed to bound HIV, which leads to their productive infection and to subsequent wide dissemination of virus. Dendritic cells probably also interact with CD8+ T cells in lymphoid organs and initiate an immune response that partially but not completely controls HIV replication [3, 7, 14].

Dr. Fauci: Fewer than 5% of HIV-infected persons show no indication of HIV disease progression and have stable CD4+ T-cell counts despite years of HIV infection; these persons are called long-term nonprogressors (Figure 6). This is in contrast to the typical HIV-infected person in whom the number of CD4+ T cells progressively declines over time. The duration of clinical latency varies, but progression to the acquired immunodeficiency syndrome typically occurs after a mean of approximately 10 years [5152]. We studied 15 long-term nonprogressors whose dates of seroconversion ranged from 1980 to 1987; all have been infected with HIV for between 8 and 15 years [53]. The blood and lymph nodes of these persons were examined for viral burden, viral expression, and integrity of lymphoid tissue architecture.

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Figure 6.
Human immunodeficiency virus (HIV) disease in progressors compared with long-term nonprogressors.closed circlesopen circles56

The course of HIV disease varies dramatically between typical HIV disease progressors ( ) and long term nonprogressors ( ). Both groups may have an initial decrease in CD4+ T-lymphocyte counts during primary infection, but long-term nonprogressors do not have continued progressive loss of CD4+ T lymphocytes during the course of HIV disease. Adapted from reference by permission of Blackwell Science, Inc., from Fauci AS. Newer concepts in the immunopathogenesis of HIV disease. Proceedings of the Association of American Physicians. 1995; 107:1-7.

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We had previously shown a consistent correlation between destruction of lymph nodes and progression of HIV disease in patients at various stages of disease progression [3]. However, despite the presence of follicular hyperplasia and germinal center formation in the lymph nodes of some long-term nonprogressors, the integrity of the architecture and stromal environment was preserved. Other long-term nonprogressors had little activation and minimal germinal center formation. Lymph nodes in the long-term nonprogressors were found to be less hyperplastic than the lymph nodes in progressors. Morphometric analysis of the proportion of lymphoid tissue occupied by germinal centers can be used to measure the state of activation of the lymph node. This proportion was found to be significantly greater in progressors who are in the early stage of disease than in persons not infected with HIV or in long-term nonprogressors. In general, lymph nodes of long-term nonprogressors maintained their normal architecture [53].

In one case, lymph node biopsy specimens taken 9 years apart showed remarkable preservation of lymph node architecture despite persistent HIV infection during the intervening period. In contrast, progressors examined after 3 to 5 years of HIV infection had clearly disrupted lymph node architecture. In progressors, HIV disease progression correlates with a decrease in the ability of lymph nodes to trap virus and an increase in the number of individual lymph node and peripheral blood mononuclear cells infected with HIV.

In addition to the morphologic differences observed in the lymph nodes, the level of trapped virions detected by in situ hybridization and by electron microscopy was, in general, much lower in the lymph nodes of long-term nonprogressors than in the lymph nodes of persons whose disease progressed. Expression of virus in individual cells was also much lower in the lymphoid tissue of long-term nonprogressors than in the lymphoid tissue of progressors.

Comparative analysis by DNA PCR showed that the mean viral burden in peripheral blood mononuclear cells of the progressors was 4000 proviral DNA copies per 1 × 106 cells compared with the long-term nonprogressors, whose mean viral burden was 729 proviral DNA copies per 1 × 106 cells. Lymph node mononuclear cell viral burden was 9000 copies per 1 × 106 cells in progressors and 1000 copies per 1 × 106 cells in long-term nonprogressors. In addition, RNA PCR examination of viral replication showed striking differences between the two groups; levels of viral replication were much lower in the mononuclear cells of long-term nonprogressors than in the mononuclear cells of progressors. Quantitative competitive PCR analysis showed the expected high levels of plasma viremia in progressors. Most long-term nonprogressors had generally low but variable levels of viremia similar to those of persons who were in the early, clinically latent stages of HIV disease.

It should be pointed out that in our cohort [53], we could isolate replication competent virus from the mononuclear cells isolated from lymph nodes of most persons, even though levels of viral burden were low. Similarly, other investigators [54] have also reported low levels of viral burden, whereas it was extremely difficult for them to isolate virus from peripheral blood mononuclear cells. Furthermore, one report described a defective virus in one of five long-term nonprogressors studied [55]. Both brisk cell-mediated and humoral immune responses have been seen in long-term nonprogressors [5354]. Therefore, on the basis of these observations, it is likely that these persons represent a heterogeneous group whose state of long-term nonprogressive disease probably results from robust immune responses against HIV, a poorly replicative virus, or both. In any event, the phenomenon of long-term nonprogression should serve as an excellent model to dissect out the complex mechanisms of HIV pathogenesis. An understanding of these mechanisms is critical for the design of strategies for therapeutic intervention and vaccine development.

Dr. Pantaleo: Building 10, Room 11N201, 10 Center Drive MSC 1876, Bethesda, MD 20892-1876.

Dr. Weissman: Building 10, Room 6A02, 10 Center Drive MSC 1576, Bethesda, MD 20892-1576.

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Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, et al.  HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993; 362:355-8.
 
Fox CH, Tenner-Racz K, Racz P, Firpo A, Pizzo PA, Fauci AS.  Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991; 164:1051-7.
 
Daar ES, Moudgil T, Meyer RD, Ho DD.  Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med. 1991; 324:961-4.
 
Clark SJ, Saag MS, Decker WD, Campbell-Hill S, Roberson JL, Veldkamp PJ, et al.  High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med. 1991; 324:954-60.
 
Safrit JT, Andrews CA, Zhu T, Ho DD, Koup RA.  Characterization of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte clones isolated during acute seroconversion: recognition of autologous virus sequences within a conserved immunodominant epitope. J Exp Med. 1994; 179:463-72.
 
Tindall B, Cooper DA.  Primary HIV infection: host responses and intervention strategies [Editorial]. AIDS. 1991; 5:1-14.
 
Piatak M Jr, Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science. 1993; 259:1749-54.
 
Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, et al.  Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1996; 373:117-22.
 
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M, et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995; 373:123-6.
 
Ascher MS, Sheppard HW.  AIDS as immune system activation: a model for pathogenesis. Clin Exp Immunol. 1988; 73:165-7.
 
Pantaleo G, Koenig S, Baseler M, Lane HC, Fauci AS.  Defective clonogenic potential of CD8+ T lymphocytes in patients with AIDS. Expansion in vivo of a nonclonogenic CD3+CD8+DR+ CD25 T cell population. J Immunol. 1990; 144:1696-704.
 
Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K, et al.  Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993; 362:359-62.
 
Harper ME, Marselle LM, Gallo RC, Wong-Staal F.  Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc Natl Acad Sci U S A. 1986; 83:772-6.
 
Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, et al.  Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994; 140:105-30.
 
Heath SL, Tew JG, Tew JG, Szakal AK, Burton GF.  Follicular dendritic cells and human immunodeficiency virus infectivity. Nature. 1995; 377:740-4.
 
Schrager LK, Fauci AS.  Human immunodeficiency virus. Trapped but still dangerous. Nature. 1995; 377:680-1.
 
Poli G, Fauci AS.  Cytokine modulation of HIV expression. Semin Immunol. 1993; 5:165-73.
 
Fauci AS.  The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988; 239:617-22.
 
Graziosi C, Pantaleo G, Gantt KR, Fortin JP, Demarest JF, Cohen OJ, et al.  Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994; 265:248-52.
 
Poli G, Kinter AL, Fauci AS.  Interleukin 1 induces expression of the human immunodeficiency virus alone and in synergy with interleukin 6 in chronically infected U1 cells: inhibition of inductive effects by the interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1994; 91:108-12.
 
Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS.  Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987; 238:800-2.
 
Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, et al.  Tumor necrosis factor α induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A. 1989; 86:2365-8.
 
Kinter AL, Poli G, Fox L, Hardy E, Fauci AS.  HIV replication in IL-2-stimulated peripheral blood mononuclear cells is driven in an autocrine/paracrine manner by endogenous cytokines. J Immunol. 1995; 154:2448-59.
 
Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994; 68:4650-5.
 
Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, et al.  Major expansion of CD8+ T cells with a predominant V β usage during the primary immune response to HIV. Nature. 1994; 370:463-7.
 
Pantaleo G, Fauci AS.  New concepts in the immunopathogenesis of HIV infection. Annu Rev Immunol. 1995; 13:487-512.
 
Zon LI, Arkin C, Groopman JE.  Haematologic manifestations of the human immune deficiency virus (HIV). Br J Haematol. 1987; 66:251-6.
 
Folks TM, Kessler SW, Orenstein JM, Justement JS.  Jaffe ES, Fauci AS. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988; 242:919-22.
 
Stanley SK, Kessler SW, Justement JS, Schnittman SM, Greenhouse JJ, Brown CC, et al.  CD34+ bone marrow cells are infected with HIV in a subset of seropositive individuals. J Immunol. 1992; 149:689-97.
 
Schuurman HJ, Krone WJ, Broekhuizen R, van Baarlen J, van Veen P, Golstein AL, et al.  The thymus in acquired immune deficiency syndrome. Comparison with other types of immunodeficiency diseases, and presence of components of human immunodeficiency virus type 1. Am J Pathol. 1989; 134:1329-38.
 
McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL.  The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988; 241:1632-9.
 
Stanley SK, McCune JM, Kaneshima H, Justement JS, Sullivan M, Boone E, et al.  Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-humouse. J Exp Med. 1993; 178:1151-63.
 
Bonyhadi ML, Rabin L, Salimi S, Brown DA, Kosek J, McCune JM, et al.  HIV induces thymus depletion in vivo. Nature. 1993; 363:728-32.
 
Aldrovandi GM, Feuer G, Gao L, Jamieson B, Kristeva M, Chen IS, et al.  The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993; 363:732-6.
 
Steinman RM.  The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991; 9:271-96.
 
Langhoff E, Terwilliger EF, Bos HJ, Kalland KH, Poznansky MC, Bacon OM, et al.  Replication of human immunodeficiency virus type 1 in primary dendritic cell cultures. Proc Natl Acad Sci U S A. 1991; 88:7998-8002.
 
Macatonia SE, Lau R, Patterson S, Pinching AJ, Knight SC.  Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology. 1990; 71:38-45.
 
Macatonia SE, Gompels M, Pinching AJ, Patterson S, Knight SC.  Antigen-presentation by macrophages but not by dendritic cells in human immunodeficiency virus (HIV) infection. Immunology. 1992; 75:576-81.
 
Karhumaki E, Viljanen ME, Cottler-Fox M, Ranki A, Fox CH, Krohn KJ.  An improved enrichment method for functionally competent, highly purified peripheral blood dendritic cells and its application to HIV-infected blood samples. Clin Exp Immunol. 1993; 91:482-8.
 
Cameron PU, Forsum U, Teppler H, Granelli-Piperno A, Steinman RM.  During HIV-1 infection most blood dendritic cells are not productively infected and can induce allogeneic CD4+ T cells clonal expansion. Clin Exp Immunol. 1992; 88:226-36.
 
Cameron PU, Freudenthal PS, Barker JM, Gezelter S, Inaba K, Steinman RM.  Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science. 1992; 257:383-7.
 
Pope M, Betjes MG, Romani N, Hirmand H, Cameron PU, Hoffman L, et al.  Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell. 1994; 78:389-98.
 
Thomas R, Davis LS, Lipsky PE.  Isolation and characterization of human peripheral blood dendritic cells. J Immunol. 1993; 150:821-34.
 
O'Doherty U, Steinman RM, Peng M, Cameron PU, Gezelter S, Kopeloff I, et al.  Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium. J Exp Med. 1993; 178:1067-78.
 
Zhou LI, Schwarting R, Smith HM, Tedder TF.  A novel cell-surface molecule expressed by human interdigitating reticulum cells, Langerhans cells, and activated lymphocytes is a new member of the Ig superfamily. J Immunol. 1992; 149:735-42.
 
Weissman D, Li Y, Ananworanich J, Zhou LI, Adelsberger J, Tedder TF, et al.  Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1995; 92:826-30.
 
Weissman D, Li Y, Orenstein JM, Fauci AS.  Both a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. J Immunol. 1995; 155:4111-7.
 
McWilliam AS, Nelson D, Thomas JA, Holt PG.  Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med. 1994; 179:1331-6.
 
Fauci AS, Schnittman SM, Poli G, Koenig S, Pantaleo G.  NIH conference. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection. Ann Intern Med. 1991; 114:678-93.
 
Lifson AR, Buchbinder SP, Sheppard HW, Mawle AC, Wilber JC, Stanley M, et al.  Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis. 1991; 163:959-65.
 
Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, et al.  Studies in subjects with long-term nonprogressive human immuno-deficiency virus infection. N Engl J Med. 1995; 332:209-16.
 
Cao Y, Qin L, Zhang L, Safrit J, Ho DD.  Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995; 332:201-8.
 
Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC.  Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med. 1995; 332:228-32.
 
Fauci AS.  Newer concepts in the immunopathogenesis of HIV disease. Proceedings of the Association of American Physicians. 1995; 107:1-7.
 

Figures

Grahic Jump Location
Figure 1.
Typical course of human immunodeficiency virus (HIV) infection.The New England Journal of Medicine

The complex, multifactorial, multiphasic, and overlapping factors of the immunopathogenic mechanisms of HIV disease are shown. Throughout the course of HIV infection, virus replicates and immunodeficiency progresses steadily, despite the absence of observed disease during the so-called clinical latency period. Immune activation and cytokine secretion vary among HIV-infected persons, sometimes increasing dramatically as disease progresses. Immune activation and cytokine secretion play a major role in pathogenesis. Adapted from reference 2 by permission of . Pantaleo et al. 1993; 328:327-35.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Perturbation of T-cell subsets during primary human immunodeficiency virus (HIV) infection: patient 1.

Analysis of the T-cell antigen receptor repertoire during primary HIV infection by a semiquantitative polymerase chain reaction assay showing a transient but marked increase in the number of circulating Vβ19+ cells acutely after HIV infection. Adapted from reference 27 by permission of Nature. 1994; 270:463-7.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Infection of the SCID-hu thymus with human immunodeficiency virus (HIV).

Human fetal thymus and liver are implanted under the renal capsule of the SCID (severe combined immunodeficient) mouse and allowed to mature over 3 to 4 months (original magnification × 15). A. Uninfected, normalappearing thymus with distinct lobes, well-defined corticomedullary junctions, and Hassall corpuscles. B. HIV-infected thymus. A primary isolate of HIV was injected intrathymically, and the tissue was harvested 3 weeks later. Note the marked thymocyte depletion, fibrosis, and infiltration with adipose tissue (original magnification × 15). C. Electron microscopic image of HIV-infected thymus showed marked dropout of thymocytes, leaving behind the network of interdigitating thymic epithelial cells (original magnification × 2300). D. Destruction of thymic epithelial cells. The thymocytes in this area of an HIV-infected thymus appear healthy, but the thymic epithelial cells are degenerating, appearing to undergo a toxic insult with resultant cell death. No HIV is visible (original magnification × 6000).

Grahic Jump Location
Grahic Jump Location
Figure 4.
Analysis of dendritic cells from human peripheral blood.[38-41]

Dendritic cells purified from peripheral blood by standard methods showed two populations with similar structure. Dendritic cells were isolated from peripheral blood mononuclear cells by density gradient centrifugation through 12.5% (weight/volume) metrizamide (Sigma, St. Louis, Missouri). The low-density cells were shown to be depleted of T, B, natural killer, and monocytic cells by specific staining with monoclonal antibodies and flow cytometry. A. Light microscopy showed that more than 90% of the cells had lobulated nuclei and multiple long cytoplasmic extensions (veils) (original magnification × 400). B. Transmission electron microscopy showed cells with long veiled processes, extensive Golgi regions, and lobulated nuclei. The individual cells shown in panels A and B morphologically represent the entire population (original magnification × 5500).

Grahic Jump Location
Grahic Jump Location
Figure 5.
Human immunodeficiency virus (HIV)-pulsed CD83+ dendritic cells can bind virus to their surfaces and transmit virus to unstimulated, autologous CD4+ T cells.IIIB6Top.closed circleBottom.IIIB6

The CD83+ population of cells with dendritic structure were purified by flow cytometry using HLA-DR brightness. Monocytes were purified by adherence to plastic for 24 hours. B cells and CD4+T cells were isolated with CD19 and CD4 magnetic beads (Dynal, Lake Success, New York) and were detached from the beads as per the manufacturer's instructions. Cells were pulsed with HIV at various concentrations for 1.5 hours at 37 °C and then washed three times. The HIV-pulsed cells were added to CD4+T cells (2 × 10 /well) and followed for released reverse transcriptase activity. CD4+ T cells and HIV-pulsed cells were mixed at a ratio of 1:10 and were followed for infection. Dendritic cells were pulsed with HIV at a multiplicity of infection of 0.01 □, 0.001 (open diamond), and 0.0001 ○. Monocytes (▵) and B cells ( ) were pulsed with HIV at a multiplicity of infection of 0.01. Cells were pulsed with HIV at an multiplicity of infection of 0.01 and were added in decreasing numbers to 2 × 10 CD4+ T cells. Peak reverse transcriptase activity of the infection is shown. RT CPM = referse transcriptase counts per minute.

Grahic Jump Location
Grahic Jump Location
Figure 6.
Human immunodeficiency virus (HIV) disease in progressors compared with long-term nonprogressors.closed circlesopen circles56

The course of HIV disease varies dramatically between typical HIV disease progressors ( ) and long term nonprogressors ( ). Both groups may have an initial decrease in CD4+ T-lymphocyte counts during primary infection, but long-term nonprogressors do not have continued progressive loss of CD4+ T lymphocytes during the course of HIV disease. Adapted from reference by permission of Blackwell Science, Inc., from Fauci AS. Newer concepts in the immunopathogenesis of HIV disease. Proceedings of the Association of American Physicians. 1995; 107:1-7.

Grahic Jump Location

Tables

References

Fauci AS.  Multifactorial nature of human immunodeficiency virus disease: implications for therapy. Science. 1993; 262:1011-8.
 
Pantaleo G, Graziosi C, Fauci AS.  New concepts in the immunopathogenesis of human immunodeficiency virus infection. N Engl J Med. 1993; 328:327-35.
 
Pantaleo G, Graziosi C, Demarest JF, Butini L, Montroni M, Fox CH, et al.  HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993; 362:355-8.
 
Fox CH, Tenner-Racz K, Racz P, Firpo A, Pizzo PA, Fauci AS.  Lymphoid germinal centers are reservoirs of human immunodeficiency virus type 1 RNA. J Infect Dis. 1991; 164:1051-7.
 
Daar ES, Moudgil T, Meyer RD, Ho DD.  Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. N Engl J Med. 1991; 324:961-4.
 
Clark SJ, Saag MS, Decker WD, Campbell-Hill S, Roberson JL, Veldkamp PJ, et al.  High titers of cytopathic virus in plasma of patients with symptomatic primary HIV-1 infection. N Engl J Med. 1991; 324:954-60.
 
Safrit JT, Andrews CA, Zhu T, Ho DD, Koup RA.  Characterization of human immunodeficiency virus type 1-specific cytotoxic T lymphocyte clones isolated during acute seroconversion: recognition of autologous virus sequences within a conserved immunodominant epitope. J Exp Med. 1994; 179:463-72.
 
Tindall B, Cooper DA.  Primary HIV infection: host responses and intervention strategies [Editorial]. AIDS. 1991; 5:1-14.
 
Piatak M Jr, Saag MS, Yang LC, Clark SJ, Kappes JC, Luk KC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science. 1993; 259:1749-54.
 
Wei X, Ghosh SK, Taylor ME, Johnson VA, Emini EA, Deutsch P, et al.  Viral dynamics in human immunodeficiency virus type 1 infection. Nature. 1996; 373:117-22.
 
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M, et al.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995; 373:123-6.
 
Ascher MS, Sheppard HW.  AIDS as immune system activation: a model for pathogenesis. Clin Exp Immunol. 1988; 73:165-7.
 
Pantaleo G, Koenig S, Baseler M, Lane HC, Fauci AS.  Defective clonogenic potential of CD8+ T lymphocytes in patients with AIDS. Expansion in vivo of a nonclonogenic CD3+CD8+DR+ CD25 T cell population. J Immunol. 1990; 144:1696-704.
 
Embretson J, Zupancic M, Ribas JL, Burke A, Racz P, Tenner-Racz K, et al.  Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature. 1993; 362:359-62.
 
Harper ME, Marselle LM, Gallo RC, Wong-Staal F.  Detection of lymphocytes expressing human T-lymphotropic virus type III in lymph nodes and peripheral blood from infected individuals by in situ hybridization. Proc Natl Acad Sci U S A. 1986; 83:772-6.
 
Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, et al.  Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994; 140:105-30.
 
Heath SL, Tew JG, Tew JG, Szakal AK, Burton GF.  Follicular dendritic cells and human immunodeficiency virus infectivity. Nature. 1995; 377:740-4.
 
Schrager LK, Fauci AS.  Human immunodeficiency virus. Trapped but still dangerous. Nature. 1995; 377:680-1.
 
Poli G, Fauci AS.  Cytokine modulation of HIV expression. Semin Immunol. 1993; 5:165-73.
 
Fauci AS.  The human immunodeficiency virus: infectivity and mechanisms of pathogenesis. Science. 1988; 239:617-22.
 
Graziosi C, Pantaleo G, Gantt KR, Fortin JP, Demarest JF, Cohen OJ, et al.  Lack of evidence for the dichotomy of TH1 and TH2 predominance in HIV-infected individuals. Science. 1994; 265:248-52.
 
Poli G, Kinter AL, Fauci AS.  Interleukin 1 induces expression of the human immunodeficiency virus alone and in synergy with interleukin 6 in chronically infected U1 cells: inhibition of inductive effects by the interleukin 1 receptor antagonist. Proc Natl Acad Sci U S A. 1994; 91:108-12.
 
Folks TM, Justement J, Kinter A, Dinarello CA, Fauci AS.  Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line. Science. 1987; 238:800-2.
 
Folks TM, Clouse KA, Justement J, Rabson A, Duh E, Kehrl JH, et al.  Tumor necrosis factor α induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proc Natl Acad Sci U S A. 1989; 86:2365-8.
 
Kinter AL, Poli G, Fox L, Hardy E, Fauci AS.  HIV replication in IL-2-stimulated peripheral blood mononuclear cells is driven in an autocrine/paracrine manner by endogenous cytokines. J Immunol. 1995; 154:2448-59.
 
Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, et al.  Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol. 1994; 68:4650-5.
 
Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, et al.  Major expansion of CD8+ T cells with a predominant V β usage during the primary immune response to HIV. Nature. 1994; 370:463-7.
 
Pantaleo G, Fauci AS.  New concepts in the immunopathogenesis of HIV infection. Annu Rev Immunol. 1995; 13:487-512.
 
Zon LI, Arkin C, Groopman JE.  Haematologic manifestations of the human immune deficiency virus (HIV). Br J Haematol. 1987; 66:251-6.
 
Folks TM, Kessler SW, Orenstein JM, Justement JS.  Jaffe ES, Fauci AS. Infection and replication of HIV-1 in purified progenitor cells of normal human bone marrow. Science. 1988; 242:919-22.
 
Stanley SK, Kessler SW, Justement JS, Schnittman SM, Greenhouse JJ, Brown CC, et al.  CD34+ bone marrow cells are infected with HIV in a subset of seropositive individuals. J Immunol. 1992; 149:689-97.
 
Schuurman HJ, Krone WJ, Broekhuizen R, van Baarlen J, van Veen P, Golstein AL, et al.  The thymus in acquired immune deficiency syndrome. Comparison with other types of immunodeficiency diseases, and presence of components of human immunodeficiency virus type 1. Am J Pathol. 1989; 134:1329-38.
 
McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL.  The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function. Science. 1988; 241:1632-9.
 
Stanley SK, McCune JM, Kaneshima H, Justement JS, Sullivan M, Boone E, et al.  Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-humouse. J Exp Med. 1993; 178:1151-63.
 
Bonyhadi ML, Rabin L, Salimi S, Brown DA, Kosek J, McCune JM, et al.  HIV induces thymus depletion in vivo. Nature. 1993; 363:728-32.
 
Aldrovandi GM, Feuer G, Gao L, Jamieson B, Kristeva M, Chen IS, et al.  The SCID-hu mouse as a model for HIV-1 infection. Nature. 1993; 363:732-6.
 
Steinman RM.  The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991; 9:271-96.
 
Langhoff E, Terwilliger EF, Bos HJ, Kalland KH, Poznansky MC, Bacon OM, et al.  Replication of human immunodeficiency virus type 1 in primary dendritic cell cultures. Proc Natl Acad Sci U S A. 1991; 88:7998-8002.
 
Macatonia SE, Lau R, Patterson S, Pinching AJ, Knight SC.  Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology. 1990; 71:38-45.
 
Macatonia SE, Gompels M, Pinching AJ, Patterson S, Knight SC.  Antigen-presentation by macrophages but not by dendritic cells in human immunodeficiency virus (HIV) infection. Immunology. 1992; 75:576-81.
 
Karhumaki E, Viljanen ME, Cottler-Fox M, Ranki A, Fox CH, Krohn KJ.  An improved enrichment method for functionally competent, highly purified peripheral blood dendritic cells and its application to HIV-infected blood samples. Clin Exp Immunol. 1993; 91:482-8.
 
Cameron PU, Forsum U, Teppler H, Granelli-Piperno A, Steinman RM.  During HIV-1 infection most blood dendritic cells are not productively infected and can induce allogeneic CD4+ T cells clonal expansion. Clin Exp Immunol. 1992; 88:226-36.
 
Cameron PU, Freudenthal PS, Barker JM, Gezelter S, Inaba K, Steinman RM.  Dendritic cells exposed to human immunodeficiency virus type-1 transmit a vigorous cytopathic infection to CD4+ T cells. Science. 1992; 257:383-7.
 
Pope M, Betjes MG, Romani N, Hirmand H, Cameron PU, Hoffman L, et al.  Conjugates of dendritic cells and memory T lymphocytes from skin facilitate productive infection with HIV-1. Cell. 1994; 78:389-98.
 
Thomas R, Davis LS, Lipsky PE.  Isolation and characterization of human peripheral blood dendritic cells. J Immunol. 1993; 150:821-34.
 
O'Doherty U, Steinman RM, Peng M, Cameron PU, Gezelter S, Kopeloff I, et al.  Dendritic cells freshly isolated from human blood express CD4 and mature into typical immunostimulatory dendritic cells after culture in monocyte-conditioned medium. J Exp Med. 1993; 178:1067-78.
 
Zhou LI, Schwarting R, Smith HM, Tedder TF.  A novel cell-surface molecule expressed by human interdigitating reticulum cells, Langerhans cells, and activated lymphocytes is a new member of the Ig superfamily. J Immunol. 1992; 149:735-42.
 
Weissman D, Li Y, Ananworanich J, Zhou LI, Adelsberger J, Tedder TF, et al.  Three populations of cells with dendritic morphology exist in peripheral blood, only one of which is infectable with human immunodeficiency virus type 1. Proc Natl Acad Sci U S A. 1995; 92:826-30.
 
Weissman D, Li Y, Orenstein JM, Fauci AS.  Both a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. J Immunol. 1995; 155:4111-7.
 
McWilliam AS, Nelson D, Thomas JA, Holt PG.  Rapid dendritic cell recruitment is a hallmark of the acute inflammatory response at mucosal surfaces. J Exp Med. 1994; 179:1331-6.
 
Fauci AS, Schnittman SM, Poli G, Koenig S, Pantaleo G.  NIH conference. Immunopathogenic mechanisms in human immunodeficiency virus (HIV) infection. Ann Intern Med. 1991; 114:678-93.
 
Lifson AR, Buchbinder SP, Sheppard HW, Mawle AC, Wilber JC, Stanley M, et al.  Long-term human immunodeficiency virus infection in asymptomatic homosexual and bisexual men with normal CD4+ lymphocyte counts: immunologic and virologic characteristics. J Infect Dis. 1991; 163:959-65.
 
Pantaleo G, Menzo S, Vaccarezza M, Graziosi C, Cohen OJ, Demarest JF, et al.  Studies in subjects with long-term nonprogressive human immuno-deficiency virus infection. N Engl J Med. 1995; 332:209-16.
 
Cao Y, Qin L, Zhang L, Safrit J, Ho DD.  Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med. 1995; 332:201-8.
 
Kirchhoff F, Greenough TC, Brettler DB, Sullivan JL, Desrosiers RC.  Brief report: absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. N Engl J Med. 1995; 332:228-32.
 
Fauci AS.  Newer concepts in the immunopathogenesis of HIV disease. Proceedings of the Association of American Physicians. 1995; 107:1-7.
 

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