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(Journal of Leukocyte Biology. 2003;74:642-649.)
© 2003 by Society for Leukocyte Biology

Macrophage HIV-1 infection and the gastrointestinal tract reservoir

Phillip D. Smith*,{dagger},1, Gang Meng*, Jesus F. Salazar-Gonzalez{ddagger} and George M. Shaw§

Divisions of
* Gastroenterology and Hepatology and
{ddagger} Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham;
{dagger} Research Service, Veterans Administration Medical Center, Birmingham, Alabama; and
§ Howard Hughes Medical Institute, Birmingham, Alabama

1Correspondence: Department of Medicine (Gastroenterology and Hepatology), 633 ZRB, 703 S. 19th St., Birmingham, AL 35294. E-mail: PDSmith{at}uab.edu


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ABSTRACT
 
Excluding parenteral transmissions, virtually all vertical and homosexual transmission of human immunodeficiency virus type 1 (HIV-1) occurs via the gastrointestinal tract. Cellular routes implicated in the translocation of virus across the epithelium include M cells, dendritic cells, and epithelial cells. Intestinal epithelial cells express CCR5 and can selectively transfer CCR5-tropic HIV-1, the phenotype of the majority of transmitted viruses. In the lamina propria, virus encounters the largest reservoir of mononuclear cells in the body. Surprisingly, lamina propria lymphocytes, not macrophages, express CCR5 and CXCR4 and support HIV-1 replication, implicating intestinal lymphocytes as the initial target cell in the intestinal mucosa. From the mucosa, virus is disseminated to systemic sites, followed by profound depletion of CD4+ T cells, first in the intestinal lamina propria and subsequently in the blood. As mucosal and circulating CD4+ T cells are depleted, monocytes and macrophages assume an increasingly important role as target and reservoir cells for HIV-1. Blood monocytes, including HIV-1-infected cells, are recruited to the mucosa, where they differentiate into lamina propria macrophages in the presence of stroma-derived factors. Although the prevalence of HIV-1-infected macrophages in the mucosa is low (0.06% of lamina propria mononuclear cells), the extraordinary size of the gastrointestinal mucosa imparts to intestinal macrophages a prominent role as a HIV-1 reservoir. Elucidating the immunobiology of mucosal HIV-1 infection is critical for understanding disease pathogenesis and ultimately for devising an effective mucosal HIV-1 vaccine.

Key Words: intestinal mucosa • lamina propria stroma • monocyte • epithelial cell • M cell


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ROLE OF THE MUCOSA IN TRANSMISSION
 
The mucosal surfaces of the gastrointestinal tract are the route by which human immunodeficiency virus type 1 (HIV-1) enters the host in virtually all vertical and homosexual transmissions. In vertical transmission, HIV-1 is inoculated into the upper gastrointestinal tract during the swallowing of infected amniotic fluid in utero, infected blood and cervical secretions intrapartum, and infected breast milk postpartum. Virus inoculated into the gastrointestinal tract of the fetus or infant likely enters the gut-associated lymphoid tissue through tonsillar and/or upper intestinal mucosa. In homosexual transmission, virus is acquired during orogenital and anogenital contact. Orogenital contact is reportedly more common than anogenital contact [1 2 3 ], but the orogenital route appears to be considerably less efficient than the anogenital route in transmitting virus [4 , 5 ], possibly as a result of the neutralizing effect of gastric acid.

The efficiency of HIV-1 transmission across the gastrointestinal mucosa is a function of donor infectiousness and recipient susceptibility. Donor infectiousness reflects the probability that the donor will transmit HIV-1 infection to the recipient. Current concepts regarding donor infectiousness are based primarily on studies of heterosexual transmission of HIV-1 via the genital tract mucosa; these concepts likely apply to transmission across the gastrointestinal mucosa as well. The infectiousness of a donor is greatest during primary and late-stage HIV-1 infection, when blood levels of virus are the highest [6 7 8 ]. High blood levels of HIV-1 are a key predictor of heterosexual transmission and appear to correlate directly with the level of virus in genital secretions and consequently the amount of virus inoculated onto a mucosal surface [9 ]. Genital tract infection with sexually transmitted pathogens and local inflammation further increases donor infectiousness, likely as a result of increased HIV-1 shedding into mucosal secretions [10 , 11 ]. Mucosal infection with opportunistic pathogens also may contribute to HIV-1 transmission. Mycobacterium avium complex (MAC), which frequently infects mucosal cells, up-regulates monocyte expression of CCR5, the coreceptor for CCR5-tropic (R5) virus [12 ], potentially augmenting HIV-1 entry into CCR5+ mucosal cells. In addition, MAC-induced production of CCR5 ligands, such as macrophage-inflammatory protein-1{alpha} (MIP-1{alpha}) and MIP-1ß as well as other chemokines [13 ], likely promotes the recruitment of additional target monocytes to sites of mucosal MAC infection. Furthermore, coinfection with HIV-1 and MAC or cytomegalovirus (CMV) up-regulates production of HIV-1 and the pathogen [12 , 14 15 16 ], conceivably amplifying local HIV-1 expression. The increased expression of CCR5 and HIV-1 may be mediated in part by pathogen-induced induction of nuclear factor (NF)-{kappa}B. The up-regulation of this transcription factor also may play a key role in MAC and CMV induction of tumor necrosis factor {alpha} (TNF-{alpha}) [12 , 17 ], itself a potent inducer of HIV-1 expression.

Recipient susceptibility to HIV-1 is influenced by mucosal integrity, genetic predisposition, and behavioral factors. Mucosal trauma during heterosexual and homosexual contact may disrupt the epithelial barrier and provide HIV-1 direct access to the microcirculation of the mucosa. Erosion or ulceration caused by sexually transmitted diseases also provides inoculated virus direct access to the mucosal microcirculation and lamina propria mononuclear cells. Mucosal infections associated with increased susceptibility include chancroid, syphilis, herpes simplex virus infection, and undiagnosed genital ulcers [18 , 19 ]. Regarding genetic predisposition, ~1% of Caucasions have a 32-nucleotide deletion in the gene that encodes CCR5 [20 , 21 ], resulting in a truncated, nonfunctional CCR5 and mononuclear cell-resistance to R5 viruses. Finally, behavioral factors, including increased frequency of sexual contacts and receptive anal intercourse, are associated with increased HIV-1 transmission [22 ].


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CELLULAR ROUTES OF HIV-1 ENTRY
 
When virus is inoculated onto intact intestinal and rectal mucosa, M cells, dendritic cells (DC), and epithelial cells are proposed cellular routes of HIV-1 entry. M cells, specialized epithelial cells overlying Peyer’s patches in the small intestine and lymphoid follicles in the colon and rectum, transport large macromolecules and certain microorganisms from their apical surface to the basolateral surface. In in vitro studies, rodent M cells [23 ] and human Caco-2-derived M cells [24 ] have been shown to transport HIV-1. However, human M cell-uptake and transport of virus in vivo have not been reported, likely due to the rapidity of the transport process and the unavailability of rectal tissue specimens shortly after inoculation. To address this issue, we have begun to use human jejunal explants to study HIV-1 transport by M cells. Using this system, we show in Figure 1 a section of human jejunal epithelium 40 min after exposure to HIV-1 and an M cell in the process of translocating an endocytotic vesicle containing an HIV-1 particle. Whether human M cells participate in HIV-1 transmission in vivo warrants further investigation.



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  		Figure 1. Human small intestinal epithelium and an M cell after in vitro exposure to HIV-1. (A) Explant of normal human jejunal mucosa after a 40-min incubation with R5 HIV-1 (10x106 cpm reverse transcriptase Bal; original, x18,000). (B) Intact jejunal epithelial cell microvilli with prominent glycocalyx and overlying cell-free Bal virions with characteristic HIV-1 envelope and core structure (original, x24,000). (C) Jejunal M cell between two epithelial cells; M cell displays faint cytoplasm and blunted, less numerous microvilli compared with the adjacent epithelial cells (original, x13,000). (D) A jejunal M cell with an endocytotic vesicle containing an intact HIV-1 virion near the apical surface (original, x27,000).

DC have been identified in rodent and macaque mucosal tissues [25 , 26 ] and in human tonsil, adenoid, and possibly colon tissue [27 , 28 ]. DC bind HIV-1 through DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (SIGN), a C-type lectin, that allows intact virus to be trapped and delivered to T cells, which can then disseminate to secondary lymphoid organs carrying virus to these sites [29 30 31 ]. DC-SIGN-bearing DC have been identified in colonic mucosa in patients with Crohn’s disease, particularly inflamed mucosa, suggesting the recruitment of circulating DC and/or maturation of local cells [32 ]. Tonsillar DC form conjugates with T cells, which together support high levels of HIV-1 replication in vitro [27 ]. However, the role of DC in mucosal HIV-1 infection in the human small intestine and colon has not been elucidated.

Epithelial cells, the most abundant cell type lining the mucosa, provide another potential route for HIV-1 entry. Supporting the notion that epithelial cells may participate in entry are studies showing that epithelial cell lines can translocate infectious HIV-1 from their apical to basolateral surface [33 , 34 ]. R5 and CXCR4-tropic (X4) viruses appear to be transferred by epithelial cell lines. However, R5 virus is isolated from the vast majority of acutely infected persons [35 36 37 ], although both R5 and X4 viruses are typically inoculated onto the mucosa. Therefore, we investigated whether primary intestinal epithelial cells, which differ phenotypically from epithelial cell lines [38 ], can selectively transfer R5 HIV-1. Using primary epithelial cells from normal human jejunum, we have shown that intestinal epithelial cells express galactosylceramide, an alternative, primary receptor for HIV-1, and CCR5, the coreceptor for R5 viruses, but not CXCR4, the coreceptor for X4 viruses [38 ]. Consistent with this phenotype, intestinal epithelial cells transferred R5 but not X4 viruses to CCR5+ indicator cells, which efficiently replicated the viruses [38 ]. Blocking and biochemical studies showed that the virus was transferred by endocytotic uptake and microtubule-dependent transcytosis. Thus, CCR5+ intestinal epithelial cells appear fully capable of selecting and transferring exclusively R5 viruses, indicating a potential mechanism, particularly in infants, for the selective transmission of R5 HIV-1 in primary infection acquired through the upper gastrointestinal tract.


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EARLY TARGET CELLS IN THE GASTROINTESTINAL MUCOSA
 
After HIV-1 has been delivered to the subepithelial lamina propria, the virus encounters the largest reservoir of macrophages in the body [39 ]. However, intestinal macrophages differ markedly in phenotype and function from blood monocytes [40 41 42 43 44 45 ] (Table 1 ), the cells from which intestinal macrophages are derived [46 47 48 ]. Specifically, intestinal macrophages do not express innate response receptors, such as the receptors for lipopolysaccharide (CD14), IgA (CD89), or IgG (CD16, CD32, CD64), and do not produce proinflammatory cytokines, including interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, TNF-{alpha}, or transforming growth factor-ß [42 ]. However, intestinal macrophages retain avid phagocytic activity for bacteria, fungi, apoptotic cells, and inert material and strong bacteriocidal function [40 41 42 ]. Thus, intestinal macrophages are unable to provide an inflammatory response to lumenal bacteria or their products, but the cells can efficiently phagocytose and kill organisms that breach the epithelium, an ideal profile for down-modulating mucosal inflammation while promoting vigorous host defense.


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  		Table 1. Unique Phenotypic and Functional Features of Intestinal Macrophages

As intestinal macrophages are derived from circulating blood monocytes [46 47 48 ], we have conducted studies with blood monocytes to define the mechanism by which intestinal macrophages develop their characteristic inflammatory anergy. Preliminary experiments indicate that lamina propria mesenchymal cells, predominantly fibroblasts, produce factors that differentiate blood monocytes in vitro into cells with the phenotype and function of intestinal macrophages [42 ]. For these studies, we generated stroma-conditioned media (S-CM), epithelial cell-CM (E-CM), and lamina propria mononuclear cell-CM (MNL-CM) from purified intestinal tissue components and cells. Monocytes exposed to S-CM but not E-CM or MNL-CM lost their innate response receptors and their ability to produce inflammatory cytokines but retained their phagocytic and bacteriocidal activity [42 ]. In addition, S-CM caused the monocytes to lose their ability to activate NF-{kappa}B, also a feature of intestinal macrophages. These findings offer a mechanism by which blood monocytes recruited to the lamina propria differentiate into intestinal macrophages. The profound inability of intestinal macrophages to respond to an array of proinflammatory stimuli likely promotes the low level of inflammation characteristic of normal intestinal mucosa. However, the retained phagocytic and cytotoxic activities allow the macrophages to scavenge for apoptotic cells and inert material and defend the mucosa against the complex array of lumenal microorganisms.

Consistent with their unique phenotype and functional profile, intestinal macrophages do not express CCR5 or CXCR4 (Fig. 2 ) and consequently, are not permissive to HIV-1 infection (Fig. 3 ) [43 44 45 ]. To elucidate the mechanism by which intestinal macrophages, in contrast to blood monocytes, develop this unique phenotype, we exposed blood monocytes to S-CM, E-CM, and MNL-CM and analyzed the cells for coreceptor expression and HIV-1 permissiveness. As shown in Figure 4 , exposure of blood monocytes to S-CM, but not E-CM or MNL-CM, down-regulated coreceptor expression and HIV-1 p24 production, as well as viral RNA and DNA expression. These findings suggest that mucosal, particularly lamina propria stromal factors induce the loss of HIV-1 permissiveness in monocytes newly recruited to the mucosa or induce these changes after HIV-1-infected blood monocytes take up residence in the mucosa. This lack of HIV-1 permissiveness, characteristic of intestinal macrophages, may explain the well-documented, low prevalence of HIV-1 mRNA-expressing macrophages in the upper gastrointestinal tract mucosa of patients with AIDS [49 ]. The lack of HIV-1 permissiveness indicates that intestinal macrophages are incapable of participating in the selection of R5 viruses in primary infection or serving as the initial target cell for R5 infection. In contrast, intestinal lymphocytes express CXCR4 and CCR5 and support replication by X4 and R5 viruses [45 , 50 ]. Thus, lamina propria lymphocytes are likely the initial target cell for HIV-1 after upper gastrointestinal tract inoculation, although the permissiveness of lamina propria lymphocytes for R5 and X4 viruses suggests that these cells also do not participate in R5 selection in primary infection.



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  		Figure 2. HIV-1 receptor and coreceptor expression on intestinal and blood mononuclear cells. Intestinal lymphocytes (left panels), macrophages (right panels), and blood monocytes (insets) were purified from the same donor and analyzed for surface CD4, human leukocyte antigen (HLA)-DR, CCR5, and CXCR4 by flow cytometry. Intestinal lymphocytes, not macrophages, express CCR5 and CXCR4 (see ref. [45 ]).



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  		Figure 3. HIV-1 replication in intestinal lymphocytes and macrophages and blood monocytes from the same donor. Intestinal lymphocytes and macrophages were cultured for 5 days in the presence of macrophage-colony stimulating factor, 1000 U/ml, and then inoculated in parallel with serial dilutions [{blacktriangleup}, tissue culture infectious dose (TCID)50 10,000; {diamond}, TCID50 1000; •, TCID50 100; {square}, TCID50 10] of Bal or IIIB HIV-1, and culture supernatants were assayed for p24 at 4-day intervals. Control blood monocytes were precultured similarly and then inoculated with Bal (Inset). The viability of each population of cells was >90% on day 20. Intestinal lymphocytes, not macrophages, support HIV-1 replication.



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  		Figure 4. Intestinal stromal cell products down-regulate monocyte HIV-1 permissiveness. Blood monocytes were incubated for 24 h with S-CM (0.5 mg protein/ml) generated from a 24-h culture of purified lamina propria stroma after the mononuclear cells had been removed by enzyme digestion. S-CM down-regulates monoycte (A) surface CCR5 expression; (B) HIV-1 p24 production (day 16 of infection with Bal TCID50, 1000); (C) HIV-1 entry (detection of HIV-1 RNA 5 h postinfection); and (D) HIV-1 reverse transcription (detection of HIV-1 DNA 24 h postinfection). Copies of cell-associated RNA and DNA corresponding to HIV-1 pol were measured by real-time polymerase chain reaction. Control monocytes in the RNA and DNA studies were stimulated with LPS (1 µg/ml) for 24 h. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase.


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HIV-1 REPLICATION IN MUCOSA AND DEPLETION OF LAMINA PROPIA CD4+ T CELLS
 
Simian immunodeficiency virus (SIV) infection of macaques has provided an important model for elucidating the early mucosal events in HIV-1 infection. In macaques inoculated orally [51 ], rectally [52 ], or vaginally [53 ], the first intestinal mononuclear cells infected with SIV are lymphocytes, and local SIV replication occurs predominantly in lymphocytes. Moreover, during early infection, SIV-infected intestinal lymphocytes are more common than infected blood lymphocytes [52 ]. The high prevalence of activated CD4+ T cells in the intestinal lamina propria may contribute to the initial, higher frequency of virus-infected lymphocytes in the mucosa compared with the blood [48 ]. Coincident with the early accumulation of SIV-infected lymphocytes in the macaque gastrointestinal mucosa is the presence of a high viral load in the mucosa, which appears to be associated with villous atrophy and malabsorption [54 ], similar to the morphologic changes and enteropathy in persons with AIDS [55 ]. Seven to 14 days after SIV inoculation, CD4+ T cells in the intestinal and colonic mucosa become rapidly and profoundly depleted, after which circulating CD4+ T cells begin to decline and eventually become depleted [52 , 54 ]. In humans, HIV-1 infection also causes depletion of CD4+ T cells in the small intestine, followed by progressive and profound CD4+ T cell depletion in the blood [56 , 57 ]. These findings from animal model and human studies underscore the central role of mucosal events in early HIV-1 infection.


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GASTROINTESTINAL TRACT MUCOSA AS A HIV-1 RESERVOIR
 
The gastrointestinal tract mucosa is the largest lymphoid organ in the body [58 ] and the lamina propria the largest reservoir of macrophages in the body [39 ]. Consequently, investigators have focused on this organ as a target for HIV-1 in primary infection, when R5 viruses are the dominant transmitted species, and in late infection, as a reservoir for HIV-1-infected macrophages. However, as discussed above, lamina propria lymphocytes, not macrophages, express CCR5 and support R5 virus replication [43 44 45 , 50 ]. Thus, intestinal lymphocytes appear to be the initial target cell for HIV-1 in the gastrointestinal tract in early HIV-1 infection.

In addition to serving as the conduit for HIV-1 entry and as the target for early HIV-1 infection, the gastrointestinal tract mucosa participates in the dissemination of newly inoculated virus. HIV-1 inoculated onto disrupted epithelium enters the intestinal microcirculation and is probably distributed widely throughout the body, whereas virus that enters the mucosa through M cells would infect lymphocytes and DC in the underlying lymphoid follicle. From the lymphoid follicle, infected T cells could disseminate to distant mucosal sites, including the esophagus [49 , 59 ], duodenum [55 ], ileum [60 ], and colon and rectum [17 , 57 , 61 ], via the receptor-mediated homing mechanism used by antigen-stimulated T cells. Infected DC could distribute virus to distant lymphoid tissues, following the migratory path of DC to lymphoid organs. HIV-1 that enters the muocsa through epithelial cells would infect local lamina propria CD4+ T cells, as described above. In each of these sites, blood mononuclear cells circulating through the infected tissue would encounter virus, potentially amplifying systemic infection.

Regardless of the route by which HIV-1 enters the gastrointestinal mucosa, primary infection is followed by a prolonged period of clinical latency that coincides with high levels of viral replication in lymphoid organs [62 63 64 ]. As a lymphoid organ, the gastrointestinal tract mucosa is presumed to support high levels of viral replication as well. HIV-1 replicates preferentially in activated CD4+ T cells [65 , 66 ], and intestinal lymphocytes display increased activation relative to nonintestinal lymphocytes [67 ], likely as a result of the lowered activation threshold of lamina propria CD4+ T cells [68 ] and the abundance of stimulatory cytokines in intestinal mucosa [69 70 71 ]. However, HIV-1 infection of purified intestinal lymphocytes results in 40–90% less HIV-1 production in vitro than infection of purified blood lymphocytes from the same donor [45 ]. Others have observed that the unfractionated mucosal mononuclear cells most susceptible to HIV-1 are CCR5+ CXCR4+ but that p24 production is greater in mucosal mononuclear cells than peripheral blood mononuclear cells [72 ], possibly reflecting differences in the purity of the target cell populations. The reduced level of virus replication in purified intestinal lymphocytes may also reflect increased tissue levels of CCR5 ligands, including MIP-1{alpha}, MIP-1ß, and regulated on activation, normal T expressed and secreted (RANTES), which down-modulate macrophage HIV-1 infection via receptor blockade [73 , 74 ]; R5 virus infection of intestinal lymphocytes could be down-modulated by the same mechanism [44 ]. However, some chemokines, such as monocyte chemoattractant protein-1, may enhance viral replication [74 , 75 ]. Thus, studies of the interaction between HIV-1 and isolated intestinal cells have provided important information on the immunobiology of HIV-1 infection of mucosal cells, but such studies do not reflect the complexity of stimulatory and inhibitory factors in the mucosal microenvironment.

In the absence of highly active antiretroviral therapy, the presence of HIV-1 in the mucosa eventually initiates a profound decline in the number of lamina propria CD4+ lymphocytes [56 , 57 ], likely the consequence of several mechanisms, including cell lysis [76 , 77 ], cytotoxic lymphocyte activity [78 , 79 ], and enhanced apoptosis [80 , 81 ]. The reduction in lamina propria CD4+ T cells in HIV-1-infected persons precedes the profound reduction in circulating CD4+ T cells [56 ], underscoring the central role of the gastrointestinal tract mucosa in initiating key events in early HIV-1 disease pathogenesis.

As mucosal and circulating CD4+ T cells are depleted, monocytes and macrophages assume an increasingly important role as target and reservoir cells for HIV-1. Factors that promote monocyte/macrophage permissiveness for HIV-1 infection include enhanced cell differentiation and activation, coinfection with opportunistic pathogens, and the presence of stimulatory cytokines [82 ]. The cumulative effect of these factors strongly influences the level of HIV-1 infection and replication in systemic mononuclear phagocytes. As blood monocytes migrate to the mucosa in response to inflammatory stimuli or to replace dead or senescent macrophages [46 47 48 ], infected monocytes could be delivered to the lamina propria among the newly recruited monocytes. Thus, in contrast to early HIV-1 infection, when the virus and infected cells move from the mucosa to systemic sites during late-stage infection HIV-1-infected blood monocytes are delivered to the mucosa, where they differentiate in the presence of stroma-derived factors [42 ] and take up residence as lamina propria macrophages. However, even after clinical AIDS is established, the number of HIV-1-infected cells among the lamina propria mononuclear cells in the upper gastrointestinal tract is surprisingly small—~0.06% of lamina propria mononuclear cells [49 ]. Despite the overall low prevalence of HIV-1-infected macrophages in the gastrointestinal mucosa and the reduced expression of virus compared with blood monocytes, the extraordinary size of the gastrointestinal tract mucosa positions infected blood monocytes recruited to the mucosa to play an important role as a reservoir for HIV-1. The close proximity of bacteria and bacterial products, the local expression of a rich array of cytokines, and the presence of endogenous mucosal factors perpetuate and amplify the reservoir function of the gastrointestinal tract mucosa in HIV-1 infection. Thus, from the initial inoculation of virus to the final stages of disease, the gastrointestinal tract plays a fundamental role in the pathogenesis of HIV-1 infection.


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ACKNOWLEDGEMENTS
 
NIH grants DK-47322, HD-41361, AI-41530, and DK-64400 and the Research Service of the Department of Veterans Affairs supported this work.

Received May 14, 2003; revised July 11, 2003; accepted July 15, 2003.


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