CYNTHIA L. BRISTOW 1. INTRODUCTION
Viruses are biological entities that do not inherently possess life since significant reproduction is dependent on internalization by a susceptible host cell. Ultimate parasitism by certain viral species allows continued replication of both the host cell and the virus, and this requires mutual equanimity. At this point in history, human immunodeficiency virus (HIV) has acquired an evolutionary state of very efficient, but not ultimate, parasitism. In fact, it is the insufficiency of equanimity between host cells and virus that produces the chronic inflammation which culminates in consummation of the mononuclear phagocyte system.
According to the 1993 classification system of HIV disease defined by the Centers for Disease Control, HIV infection can be described in terms of three categories. Category A is defined as a mononucleosis-like syndrome associated with seroconversion for HIV antibody. Category A is accompanied by acute viremia occurring 2-4 weeks after exposure and which is no longer detected systemically after the first 3 months. The initial viremia, represented by passage of the virus between heterologous cells (sexual
CYNTHIA L. BRISTOW • McLendon Clinical Laboratories, Department of Pathology and Laboratory Medicine, University of North Carolina Hospitals, Chapel Hill, North Carolina 27514.
Human Retroviral Infections, edited by Kenneth E. Ugen et al. Kluwer Academic / Plenum Publishers, New York, 2000.
transmission), is recognized and contained, but not cleared, by the mononuclear phagocyte system. A postacute, asymptomatic period as long as 10 years is characterized by diminutive systemic viral replication and is followed by Category B, the onset of constitutional symptoms which concurrently manifests systemically with a second chronic viremia. The second principal viremia, represented by passage of the virus between autologous cells (autol-ogous transmission), is not contained, and it is evident that both the virus and infected cell populations have dramatically changed since the initial viremia. Finally, Category C is defined as the onset of multiple opportunistic infections and acquired immunodeficiency syndrome (AIDS) and results in death after 2-3 years.
The differences which exist during heterologous and autologous transmission are readily demonstrated by culturing susceptible cells in hetero-logous versus autologous serum (Table I). A primary patient isolate (third passage) was incubated with peripheral blood mononuclear cells cultured in autologous serum, heterologous human serum, or fetal calf serum. The 50% tissue culture infectious dose (TCID50) under these conditions decreased as the incompatibility between cells and serum increased.
Investigation by virologists worldwide has greatly increased our understanding of the structural and functional characteristics of HIV. On the other hand, limited information is available on the precise host cell characteristics which exist during the moment of susceptibility. For example, host cells and their receptors have been examined with little attention to the effect of the microenvironment on secondary receptor interactions. Significantly, neither the host cells which have the capacity to become susceptible nor the environments where they reside are uniform, and this would suggest diversity during cellular uptake of HIV with a complexity now only scarcely imagined. The diversity of HIV infectious units, target cells, and conditions under which they make contact are inspected in this chapter with the intent of expanding our conceptualization of molecular events involved during the initiation of infection.
Differences between Autologous and Heterologous Transmission"
Differences between Autologous and Heterologous Transmission"
Heterologous human serum
Fetal calf serum
"Viral titer determined by p24 capture following in vitro infectivity using a primary HIV patient isolate with four unrelated subjects cultured in serum from different sources. ND, Not done.
"Viral titer determined by p24 capture following in vitro infectivity using a primary HIV patient isolate with four unrelated subjects cultured in serum from different sources. ND, Not done.
The architecture of a virion is designed to allow its safe entry into a host cell with minimal disturbance of host cell physiology, and this requires concerted contact in the milieu where the cell resides. In the majority of cases, the parameters of HIV infectivity have traditionally been measured using transformed target cells (cell lines) or peripheral blood target cells cultured in the presence of fetal calf serum, as opposed to human serum or mucosal secretions which are known to impact infectivity in vitro as well as in vivo. Neither the infectious unit, the initially infected cell population, nor the conditions in the environment during sexual transmission of HIV are definitively understood.
There is little evidence as to whether sexual transmission occurs via the cell-free versus cell-associated form of HIV. That seminal plasma is toxic to cell-free HIV1 suggests that as a result of sexual transmission, the target cell of the anorectal junction or genital tract is likely to receive the virus associated with either spermatozoa,2 donor, or recipient phagocytic cells. It can be speculated that sexual transmission may involve phagocytosis or intercellular fusion of cell-associated virus; however, the identity of molecular mechanisms involved during sexual transmission have proven technically prohibitive.
The transmissibility of cell-associated virus to non-CD4+ mucosal target cells, e.g., epithelial cells,3 has been demonstrated; however, the histoin-compatibility of the virus or virus-associated donor cell which is transmitted through sexual contact suggests that the selectively dominant recipient target cell is most likely a mucosal antigen-processing cell, i.e., macrophage-like cell (Mo/M^). Evidence has suggested that the Langerhans type of tissue M^ can be the initial recipient target cell in sexual transmission,4,5 and similar phagocytic cell types are implicated in distinct tissues.
The names of specialized phagocytic cells derived from bone marrow promonocytes vary according to their location: Langerhans cells in the skin; macrophages (M^) in the bone marrow, lymphoid tissue, and serous cavities; monocytes (Mo) in the blood; histiocytes in connective tissue; microglia in the nervous system; alveolar macrophages in the lungs; and Kupffer cells in the liver.6 The antigen-processing cell population including the peripheral monocyte gives rise to the tissue macrophage referred to as the histiocyte. The antigen-presenting cell population, referred to as the dendritic cell, is generally not phagocytic. Antigen-presenting cells can be divided into three subsets: follicular dendritic reticulum cells, interdigitating reticulum cells, and Langerhans cells. Circulating monocytes, tissue histiocytes, and macrophages normally do not proliferate except in conditions of inflammation.
Langerhans cells originate in bone marrow and reside in the suprabasal and spinous layers of epithelium, where M^ lymphocytes, and other immune cells are located in the subepithelial lamina propria. These cells represent 2-5% of the epidermis and are two- to three-fold more frequent in nonkeratinized than keratinized epithelium.7 It has been shown that depletion of Langerhans cells from cutaneous surfaces allows access of antigen to the systemic immune apparatus as a tolerogenic, rather than an immunogenic signal.8 After processing antigen, Langerhans cells migrate to and reside in the proximal lymph nodes where antigen is presented to T lymphocytes.9 During migration to the lymph nodes, Langerhans cells have been reported to undergo phenotypic changes correlating with differentiation from predominantly antigen-processing to predominantly antigen-presenting interdigitating dendritic cells.10 Differentiation has been reported to be enhanced by products of T lymphocytes and M^.11
In common with a subset of Mo/M^, Langerhans cells can possess surface CD4, major histocompatibility complex (MHC) , Fc receptors, and C3 receptors.712 The involvement of each of these receptors in facilitating HIV infectivity has been implicated.13-16 It has been reported that trypsiniza-tion of Langerhans cells during isolation from tissue results in enhanced binding of HIV envelope proteins in a non-CD4-dependent manner,17 suggesting the possibility that the initiating infection might not necessarily be a CD4-dependent event. As would be predicted, loss of Langerhans cells has been reported to occur concomitantly with severity of oral hairy leukoplakia and candidiasis as well as HIV-associated and non-HIV-associated periodon-tal disease,7 supporting the participation of these cells in protecting against the attendant mucosal pathology of HIV infection.
It was reported that certain HIV-1 clades preferentially infected Langerhans cells in vitro,5 and this suggests that either more than one subtype of tissue M^ might be involved in transmission in different settings or the in vitro tissue culture conditions were selective.
Mucosal secretions are a cardinal determinant in systemic immune responsiveness following mucosal pathogenic insult. The overall purpose of mucosal lymphoid tissue is to localize antigen and prevent systemic involvement. In fact, systemic unresponsiveness is a common consequence of mucosal antigen exposure. Evidence suggests the mucosa of an HIV-infected individual has atypical immune activity. Synthesis of immunoglobulin G (IgG), but neither IgA nor IgM, having specificity for HIV-1 has been reported in the genital tracts of male and female seropositive individuals.1819 The loss of mucosal secretory IgA correlates with clinical presentation, suggesting the loss of protective immunity in the mucosa.20 Increased IgG in the mucosa suggests a breakdown in the mucosal barrier and concomitant inflammation, and this correlates with the clinical spectrum of HIV infection.
The state of the mucosa of the recipient partner is also not likely to be quiescent. It has been found in many epidemiologic studies that risk of sexual transmission of HIV increases with number of partners, and may increase with number of encounters with the same partner.2122 The incidence of transmission after exposure with a single partner has been linked to increased viral inoculum with greater likelihood during the second principal viremia of advanced AIDS in the infected partner. Even though excessive viral inoculum increases the probability of a "hit" in an otherwise quiescent mucosal environment, there is a conspicuous lack of evidence supporting infection following a single exposure.21
Three situations for optimum sexual transmission have been proposed: (1) in repeated exposure with many partners, a state of inducible immunity may preexist in the recipient mucosa (lymphoblasts, activated M^, neutrophils, cytokines, immunoglobulin) ; (2) in repeated exposure with a single partner, excessive viral inoculum in the presence of the concomitant inflammatory components of seminal plasma (immunoglobulin, complement activation, cytokines, lymphoblasts, activated M^, neutrophils) may perturb the microenvironment of the target cell population; or (3) the viral genome, having interacted with or integrated with the recipient tissue during a prior exposure, may be taken up by a permissive cell in the presence of activating cofactors (neutrophils, cytokines, coinfecting pathogens, endo-toxin). Each of these proposed conditions suggests that the state of the mucosal target cell population during the conclusive infectious event is probably altered from its normal physiological state.
Besides the perturbing effects of repetitive pathogenic insult to the mucosal environment, there is the significant, yet poorly understood contribution of the mucosal secretions during HIV encounter. Transmission of Simian immunodeficiency virus (SIV) by the genital route in the rhesus macaque has been demonstrated in the cell-free, but never in a cell-associated manner, and the importance of seminal plasma has been postulated.23 Immunosuppressive mechanisms of saliva, seminal plasma, and other mu-cosal secretions have not been carefully compared, independently or in combination, even though there is ample evidence for such an effect. Seminal plasma has immunosuppressive character not only as a mechanism to facilitate fertilization by these gametes in an immunologically unfriendly environment, but also to protect spermatozoa against autoimmunity.24
Predominant in seminal plasma are proteinases and proteinase inhibitors, some of which have been implicated in HIV internalization.25-29 One proteinase in canine seminal plasma accounts for over 90% of the total protein.30 A primary immunosuppressive component of seminal plasma has been identified as a prostasome. Prostasomes are multilamellar vesicles which, in addition to the potentially immunosuppressive effect of lipid components, manifest surface-associated immunoreactive components including IgG, IgA, purine nucleotides, and enzymes. Prostasomes are rapidly bound and internalized by neutrophils and M^, but not lymphocytes, and internalization results in decreased superoxide anion production and phagocytosis of latex particles.31 The potential for prostasomes or other noncel-lular vesicles to participate in transmission of HIV has not been investigated.
Saliva has been shown to be immunoregulatory. It has been found that oral tolerance results from ingestion of antigen by inducing T cell, but not B cell, suppression in humans and has been suggested to be a mechanism for avoiding immunoreactivity to certain foods.32 Prevention of atopic reactions to food has also been proposed as a role for the immunosuppressive effect of human milk and colostrum.33
Not surprisingly, unique functional and therefore structural attributes of each tissue and organ dictate that the generic qualities of immunity be fashioned to fit the special needs of each tissue and organ.34 The regionally specialized gut-associated (GALT) , bronchus-associated (BALT), nasalassociated (NALT), or mucosal-associated lymphoreticular tissue (MALT) migrate to the draining lymph nodes, thoracic lymph duct, bloodstream, and finally the lamina propria representative of their origin, where they mature and produce IgA-secreting plasma cells. It has been reported that the mucosal immune system is compartmentalized in a manner resulting in preferential distribution of lymphocytes to mucosal regions adjacent to the site of immunization.35 This suggests the possibility that HIV could prime the recipient and HIV-specific plasma cells might establish in the local environment prior to infection. Recipientderived or donorderived IgG or IgA might facilitate or even be requisite during the initial infectious event. Evidence has been found for the involvement of host factors during disease progression following cell-free, intravenous SIV infection of macaques, and these factors appeared to influence infection outcome equivalently in vivo and in vitro.36
In addition to the migration of infected cells through the lymphatics, the initial viremia is manifested in blood, which results in global distribution of infected cells, primarily T lymphocytes.37 It has been suggested that the primary role of GALT is twofold: to prime an immune response (antigen-
processing and antigen-presenting) and to amplify a response by dissemination of antigen-specific lymphocytes (antigen-presenting).38 By analogy, MALT might be involved in priming as well as in amplification of a response already primed at another site. Once infection has been established, the diffuse lymphatic tissue of the mucosal surfaces may be seeded with macrophages and lymphocytes capable of releasing viral particles from the basal and/or apical surfaces, initiating a chronic, carrier state of infection. The manifestations of pathology at mucosal surfaces (oral, upper respiratory, gastrointestinal) may result from the release of inflammatory viral proteins and host mediators to the epithelial cell surface and interstitium of the mucosa.
In summary, neither the infectious unit, target cell, nor the environment that exists during sexual transmission has been clearly identified. At best, it can be speculated that cell-associated HIV is transmitted to a mucosal phagocytic cell in an environment containing products characteristic of inflammation. The significance of previously identified HIV cofactors (B-chemokine receptors) and receptors (CD4 and proteinases) during sexual transmission has not been explored.
Once the initial viremia has abated, the infection becomes difficult to detect and symptoms are minimal. The predominant infected cell in tissue is the M^ and the predominant infected cell in blood is the CD4+ T lymphocyte.37 The in vivo CD4+ T lymphocyte population is maintained at a functionally intact, but relatively diminished level, which persists until an inevitable, unascertained precipitous event heralds the final dysregulation of immune competence. This threshold is defined by a capacitance which may be affected by both lymphocytes and Mo/M^ directly or indirectly; however, the properties determining capacitance are precisely the mechanisms of transmission between heterologous cells and between autologous cells.
The fate of the infected Mo/M^ is not clear. Ultrastructural analysis of HIV-infected Mo/M^ demonstrates little or no cytopathic effects, and little or no expression of viral protein or release of virions from the cytoplasmic membrane.3940 Instead, HIV accumulates within intracellular vacuoles derived from the Golgi complex, assembles, and buds from the vacuolar membranes.41 Exocytosis into the extracellular milieu appears suppressed, and infected cells can persist in tissue for months containing infectious particles within the intracytoplasmic vacuoles.37 When these cells become stimulated, cell-free virions are released which have been demonstrated to have dual tropism, infecting monocytes and T lymphocytes equivalently.37
Activation of Mo/M^ was defined by Adams and Johnson42 as the acquisition of competence to complete a complex function such as the destruction of microbes or tumor cells. After entering tissues, M^ generally remain inactive until stimulated by one or a combination of inductive signals. Receptor ligation results in one of several inductive or suppressive cascades of signal transduction which ultimately impact on specific genes. Transcription of HIV DNA has been found to be dependent on the specific characteristics of the region of the cellular genome in which the proviral DNA has integrated,43 and this reflects the specificity of the activation cascade initiated by receptor ligation.
The fate of the infected T cell is ultimately cell death through mechanisms including apoptosis, cytolysis, and syncytia formation,44 and this suggests that transmission of HIV to T lymphocytes in circulation can be either cell-free or cell-associated. Evidence has suggested unidirectional transfer of HIV from the Mo/M^ to the T lymphocyte37; however, phagocytosis of infected T cell debris by neutrophils, M^, or other phagocytic cells could influence autologous transmission.
Significantly, as the syndrome develops, the virus adopts host cell receptors and ligands,1445 and several of these have been shown to enhance infectivity of Mo/M^ and T and B lymphocytes.46,47 Whereas the viral and cellular membranes and coupled receptors during autologous transmission are derived from autologous cells, these are derived from heterologous donor cells during sexual transmission. Therefore, the infectious unit can be cell-associated or cell-free during autologous transmission, and the capacity for immune recognition may be masked by autologous membrane components.
Receptor ligation by cells in the mononuclear phagocyte system is tightly regulated to minimize the potential for autoreactivity. Ligation of lymphocyte receptors in an inappropriate order induces apoptosis. To hijack a cell requires a threshold of viral compatibility that will permit replication to occur prior to death of the cell. For this reason, the physiological role of a cell-surface molecule is preempted by its ligation with a virion. A molecule that acts as a proteinase physiologically might act as aviral receptor, and a molecule that acts as a receptor physiologically might act to colocalize the virus without directly acting as a viral receptor. The temporal and topographic parameters of receptor ligation allow multiple signaling cascades to be produced permitting the resulting multiplicity of discrete cell functions. This implies that the ligation of a signaling receptor by a virion requires uncoupling of the activating signal at some subsequent step.
The saturable and specific binding of HIV to CD4 and ratedependent infectivity of CD4+ T lymphocytes1348 in vitro support the involvement of the CD4 receptor during infection of T lymphocytes with cell-free virus in vivo. A lack of cellular activation in response to CD4 ligation has been demonstrated.4950 Evidence for unique CD4 involvement during internalization by Mo/M^ is not quite so convincing.51-53 Evidence suggests that HIV permissiveness can be conferred to fibroblasts,15 CD4-CD8+ T lymphocytes,54 and epithelial cells and skeletal muscle cell55 in a CD4-independent manner through receptors for IgG or C3. A family of chemokines has been demonstrated to influence infectivity both in vitro56 and in vivo.51 Although strong evidence suggests the influence of chemokine receptors during HIV inter-nalization, a direct interaction between these receptors and HIV has not been found. The involvement of additional host-specific molecules has been proposed,295859 and it has been empirically demonstrated that che-mokine receptors lack the capacity to definitively confer susceptibility.60
In situ infection of Mo/M^ could occur in skin, bone marrow, the serous cavities, blood, connective tissue, nervous system, lungs, liver, and lymphoid tissue. By Southern blot hybridization, large quantities of HIV DNA are found in the lymph node and brain, but not lysates of lung, liver, or spleen.61 Application of more sensitive molecular genetic techniques in comparative analysis of HIV burden in Mo isolated from peripheral blood and M^ isolated from bronchoalveolar lavage fluid during the asymptomatic period has revealed that the proviral burden is substantial and equivalent, but that levels of expression are minimal.62 Evidence suggests that alveolar M^ from HIV-infected patients rarely contain the HIV-1 p24 protein or HIV-1 RNA, but do exhibit proviral DNA.63 Alveolar M^ from these infected individuals were frequently found to produce infectious virions when induced by a combination of cytokines. Blood monocytes that traffic to the respiratory tract in response to infection or inflammation were significantly less susceptible to HIV infection than the resident alveolar M^. The quiescence of HIV in infected M^ can occur on at least two levels: transcription of integrated proviral DNA and release of virus sequestered within vacuoles.
The virions released by the infected T lymphocytes have not been found to have monocytic tropism in vitro,31 and this suggests that any systemic uptake of virus by Mo/M^ may involve a different process, e.g., phagocytosis. Infected progenitor cells can be detected in bone marrow in a subset (14%) of seropositive individuals,64 and these cells contribute to the infected cell population in circulation in these individuals. A possible site of infectivity of Mo/M^ is during transmigration from circulation into tissue through the lamina propria of endothelium containing resident HIV-infected Mo/M^.
In skin biopsies of HIV-infected individuals, Langerhans cells are reported to demonstrate altered morphology, and viral particles have been shown to bud into the intercellular space between Langerhans cells and adjacent epithelial cells.65 This suggests that infection of Langerhans cells during the second viremia may not induce their migration to regional lymph nodes, but that released viral products might subsequently infect cells located in the lamina propria with focal bystander cytopathology of the epithelial cells.
Evidence now suggests the predominant site in autologous transmission may be lymphoid tissue.66 Lymph node biopsies in the SIV model suggest that virus can be detected by the seventh day postinoculation of cellfree virus, and is exclusively cell-associated.6768 Binding of HIV to follicular dendritic cells has been determined to be C3-dependent, and not CD4 dependent.69 The precipitous event which heralds the second principal viremia may be the depletion of interactive immune components not directly related to the CD4+ cell population. Instead, these components may be related to the immune containment of HIV, e.g., lymph node architec-ture66 or serum components such as inhibitors of complement activation and cytokines.
Langerhans cells and interdigitating cells are found in the cortex of the lymph node (the T cell zone), whereas the dendritic cells are located in the germinal centers (the B cell zone). The germinal centers of lymph nodes are primarily composed of memory B lymphocytes, but T lymphocytes and M^ can be demonstrated. Antigen localization by interdigitating and dendritic cells is a mechanism for concentrating antigen to regions with heavy lymphocyte traffic and allows clonal selection and expansion. In a primary response, the germinal center is a highly active site for blast transformation, cytokine release, and M^ recruitment. In HIV infection, localization of HIV to the germinal centers of lymph nodes would optimize conditions for transmission of cell-free HIV from M^ to lymphocytes. M^ within germinal centers contain a distinctive type of phagolysosome, the tingible body, which includes nuclear material of phagocytized lymphocytes70 providing a mechanism for countertransmission of cell-associated HIV from T lymphocytes to M^. Further, clonal selection, expansion, and dissemination of immunoreactive cells would vary depending on variation in HIV antigens as well as on variation in the residual functionally active resident cells.
In summary, the infectious unit in autologous transmission may be cellfree or cell-associated. The primary target cells during the asymptomatic period appear to be M^ and lymphocytes located in the germinal cells of lymph nodes where inflammatory immune activity could permit transmission of cell-free HIV in a CD4-dependent manner or cell-associated HIV in a CD4-independent manner. During the second principal viremia, the CD4+ T lymphocyte population has been significantly depleted suggesting the final primary target cells are the Mo/M^.
The infectious units, target cells, and environments during sexual transmission and autologous transmission are fundamentally different. The infectious unit during sexual transmission is probably cell-associated and histoincompatible, whereas the infectious unit during autologous transmission may be cell-free or cell-associated and host-adapted. The target cell during sexual transmission is probably a mucosal phagocytic cell. The target cells during autologous transmission are probably Mo/M^ and T lymphocytes in lymphoid tissue and finally in circulation. The mucosal environment during sexual transmission is probably inflammatory and possibly facilitated by inflammatory mediators. The lymph node environment during autologous transmission is probably inflammatory and possibly facilitated by cell death. Chronic nonspecific and HIV-specific inflammation, at the expense of protective immunity for commonly encountered pathogens, results in depletion of immune resources, and finally immunodeficiency.
Understanding viral-internalization steps is paramount to intervention in the spread of HIV. Our previous attempts to define the molecular mechanisms involved in viral internalization have used target cells and infectious units derived from heterologous peripheral blood cells and cultured in the presence of calf serum, conditions which we now recognize as inadequately representing either sexual or autologous transmission. HIV drug susceptibility has traditionally been determined in a similar manner, sometimes leading to artefactual interpretations of efficacy, e.g., recombinant soluble CD4,71-73 hyper gamma globulins,74 and vitamin C.75 Our knowledge regarding the target cells, infectious units, and physiological conditions during transmission is evolving, and thus we are poised to discover the precise molecular mechanisms that define the conundrum of chronic HIV infection and AIDS.
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