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Differential Mucosal Susceptibility in HIV-1 Transmission and Infection

N.M. Moutsopoulos, T. Greenwell-Wild, and S.M. Wahl^*

Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Building 30, Rm. 320, 30 Convent Dr., MSC 4352, Bethesda, MD 20892-4352

Correspondence: ^* corresponding author, smwahl{at}dir.nidcr.nih.gov, USA

	Abstract

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
HIV infection occurs primarily through mucosal surfaces, indicating that protection at mucosal sites may be crucial in prevention and treatment. The host innate and adaptive immune elements provide a level of protection, which differs between mucosal compartments, and appears to be most successful in the oral environment, where transmission is rare. In addition to the distinct oral mucosal architecture and cellular constituents, oral fluids, unlike other mucosal secretions, are rarely a vehicle for HIV infection. Multiple soluble factors may contribute to this antiviral activity, including neutralizing antibodies, secretory leukocyte protease inhibitor (SLPI), antiviral peptides such as defensins and cystatins, glycoproteins including thrombospondin and lactoferrin, and complement components. Understanding the antiviral activities of these and other potential resistance factors is becoming increasingly important in attempts to design treatments in the era of HAART resistance. In this regard, the mechanism of anti-HIV action of SLPI has recently been further elucidated by the discovery of its binding protein/receptor, which plays a key role in the infection of macrophages and may consequently be a novel therapeutic target. Continued elucidation of the unique features of mucosal HIV immunology is essential for understanding HIV pathogenesis and for developing effective vaccines and therapeutics.

KEY WORDS: Monocytes • macrophages • saliva • mucosa • SLPI

	Introduction

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
Key events in the course of human immunodeficiency virus (HIV) infection and AIDS pathogenesis occur at mucosal sites. The mucosa represents a primary portal of entry for the virus, the initial and predominant site of viral replication and amplification, and a major location for CD4+ T-cell depletion, leading to immune deficiency (Veazey et al., 1998; Brenchley et al., 2004). Nonetheless, the probability of infection per contact is relatively low in the genital or gastrointestinal mucosa (0.0002 to 0.01) (Royce et al., 1997; Gray et al., 2001), and even lower in the oral environment (Vittinghoff et al., 1999), suggesting the presence of potential protective mechanisms. Such a defensive role, albeit not impenetrable, as well as recognition that the mucosa is a major depot of virus once transmission does occur, implicates HIV infection/AIDS as a mucosal disease, and therefore, a treatment target. To this end, intense investigations are ongoing as investigators attempt to understand mucosal immune defenses to mimic or enhance these pathways in the design of therapeutics and vaccines. In this review, we will focus on differential protective mechanisms that have recently been dissected and are present in mucosal compartments, particularly the relatively resistant oral mucosa, which may also provide promising insights for intervention strategies.

	Mucosal Susceptibility: HIV Transmission and Localization

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
The predominant mode of HIV transmission is through mucosal surfaces (Milman and Sharma, 1994; Smith and Wahl, 2005), particularly genital and gastrointestinal tract mucosae. Studies of simian immunodeficiency virus (SIV) transmission in macaques have shown that, in the absence of epithelial damage, free SIV can infect via the rectal, vaginal/cervical, penile urethra, or pharyngeal and upper gastrointestinal mucosa (Kozlowski and Neutra, 2003; Maher et al., 2004). It should be noted that SIV is a highly infective virus, and the viral inoculum used in animal experiments is very high. In humans, for most heterosexual transmissions, the genital tract mucosa is the site of viral entry, whereas for vertical transmissions (mother-to-fetus) and infections resulting from oro-genital and ano-genital contact, the gastrointestinal tract is the portal. The exact cellular and molecular events involved in the initial viral transmission continue to be dissected (Bomsel and David, 2002; Smith and Wahl, 2005), and information regarding interactions of HIV or HIV-infected cells with epithelial surfaces of the human mucosa comes mostly from in vitro experimentation. Nonetheless, it is understood that HIV transmission via intact undamaged mucosal surfaces is dependent on survival of virus and/or infected cells in mucosal secretions, and successful transport across the epithelial barrier to facilitate access to susceptible target cells.

In the absence of mucosal disruption from infection or trauma, HIV exploits the normal antigen-uptake mechanisms designed for immunological monitoring (Fig.). In stratified squamous epithelia such as the foreskin, vagina, oral mucosa, tonsil crypts, and anal canal, antigen-presenting cells may capture the virus. Motile dendritic cells (DC) can reach into the narrow epithelial spaces (Geijtenbeek et al., 2000) or even extend to the outer limit of the epithelium and trap the viral envelope gp120 through a C-type membrane lectin (dendritic cell-specific ICAM-3 grabbing non-integrin, DC-SIGN) (Geijtenbeek and van Kooyk, 2003). In simple or columnar epithelia, such as those of the small intestine, endocervix, and rectum, however, intra-epithelial spaces are sealed with tight junctions. In these locations, specialized epithelial M-cells transport antigens in vesicles across the epithelial barrier (Kozlowski and Neutra, 2003) to vulnerable cells in the underlying lymphoid follicle (Fig.).

View larger version (38K): [in this window] [in a new window]   Fig. - Potential routes of HIV mucosal entry. Multiple access routes may be utilized by HIV to gain entry through the mucosa, the most common route of HIV transmission. (1) The virus may target GalCer on the epithelial cell apical surface and enter the mucosa via epithelial cell transcytosis. (2) M-cell transport of virus may occur from the luminal surface to the subepithelium. (3) Dendritic cell recognition and capture of HIV through a gp120-DC-SIGN interaction leads to DC transport/presentation of virus to susceptible target cells. (4) Due to mucosal trauma, infection, or ulceration, the virus may gain access across the damaged epithelium directly to resident or newly recruited and highly susceptible target CD4+CCR5+ T-cells and macrophages. (5) In trauma/co-infection breach of epithelial integrity, the virus may gain access across the epithelium to the mucosal microcirculation and then disseminate systemically.

Despite shared pathways underlying mucosal HIV transmission, differential susceptibility to infection is documented in separate mucosal compartments. Multiple parameters may contribute to the relative susceptibility or resistance of a mucosal site to HIV entry. For example, different rates of exposure occur in each location (Royce et al., 1997), architectural features are unique (Brenchley et al., 2004), and distinct local environmental factors, which influence the vulnerability and composition of the target cell populations, are apparent (Smith and Wahl, 2005). Mucosal trauma, inflammation, and ulceration may disrupt the epithelial barrier and provide HIV with direct access to the mucosal microcirculation and/or provide directional signals to recruit highly susceptible, activated inflammatory monocytes and T-cells (Milush et al., 2004) (Fig.). Moreover, these recruited cells may be bearing virus as they enter the mucosa. Also contributing to susceptibility of the gastrointestinal tract is the high percentage of resident CD4+ T-cells expressing CCR5 (> 50%), compared with lymph nodes, in which only 5–10% of the CD4+ T-cells are CCR5+, or the peripheral blood, where 10–30% are CCR5+ (Brenchley et al., 2004). Furthermore, the GI tract contains a significantly higher proportion of activated Ki67+ (proliferation/activation marker) T-cells (Brenchley et al., 2004) that may propagate infection.

In a cross-sectional study of HIV-infected women, the role of the local mucosal environment in viral susceptibility was examined (Greenwell-Wild et al., 2006). HIV RNA and infectious virus were monitored in systemic and mucosal compartments and correlated with innate and adaptive host immune mechanisms. Although HIV RNA could be detected in either the oral cavity or the genital tract in a subset of women in the absence of detectable blood RNA, in most cases there was a correlation between blood and mucosal HIV RNA levels. However, HIV RNA levels could be substantial in mucosal sites without detection of any infectious virus, evidence that, in addition to systemic factors, the local mucosal environment may influence viral replication, shedding, and/or transmission. Consistent with this notion, mucosal HIV shedding appears to be influenced by a multiplicity of systemic and local factors. For example, a decrease in oropharyngeal viral shedding has been associated with antiretroviral therapy and high CD4 counts, as well as tonsillectomy (Zuckerman et al., 2003). Antiretroviral therapy also appeared to influence HIV levels in rectal and seminal fluids, although highest RNA levels were associated with rectal mucosal secretions (Zuckerman et al., 2004), underscoring the importance of the local environment in HIV susceptibility.

	Differential Protection at Mucosal Sites

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
Both innate and adaptive immune responses are engaged in defense against HIV infection, although the innate immune responses are most crucial in early stages of HIV transmission. Cellular responses as well as secretion of soluble factors have been implicated in antiviral defense. The immune cells present at sites of infection demonstrate unique protective properties. For instance, gamma delta () T-cells are involved in mucosal protection and lysis of HIV- or SIV-infected target cells (Wallace et al., 1996), whereas NK cells function as effector cells in the early innate response and may respond to the loss of MHC class I expression of virally infected cells (Lehner, 2003). CD8+ T-cells may be pivotal, in that CD8+ T-cells from long-term non-progressors with HIV-1 infection generate -defensins-1, -2, and -3 that inhibit HIV replication (Lehner, 2003). The resident DCs, macrophages, and T-cells in subepithelial tissues also secrete numerous chemokines and cytokines that can interfere with HIV transmission and replication. Extensive evidence supports the role of the CC chemokines (RANTES, MIP1-, MIP1-ß) as entry inhibitors, through their ability to bind specifically to the HIV co-receptor CCR5 and down-modulate infection (Cocchi et al., 1995). While these studies offer important information on the immunopathogenesis of HIV-1 infection of mucosal cells, the complex interactions between inhibitory and stimulatory factors in the microenvironment in vivo are ill-defined.

Innate molecules with anti-HIV activity
The innate, secreted molecules that may be involved in fending off HIV, as well as other invading micro-organisms, include the complement proteins, antimicrobial peptides, and various glycoproteins (Table). The complement complex of proteins is one of the main components of the innate response and functions in the lysis and opsonization of pathogens. Components of the complement system serve as chemoattractants that contribute to the generation of a specific immune response. In HIV infection, complement becomes activated via the alternative (Thielens et al., 2002) as well as the classic pathway, leading to HIV opsonization, although not always successfully, due to mechanisms that the virus has evolved to escape opsonization (Stoiber et al., 2005).

In addition to antimicrobial peptides, several glycoproteins found in mucosal secretions have been implicated to have anti-HIV actions. Thrombospondin, a high-molecular-weight extracellular matrix glycoprotein, inhibits HIV by aggregating the virus and inhibiting entry (Crombie, 2000), whereas lactoferrin, an iron-binding glycoprotein secreted by neutrophils, binds to gp120 and inhibits fusion and entry of the virus (Swart et al., 1998). High- and low-molecular-weight mucins (MG1, MG2) appear to displace the viral envelope glycoprotein gp120 from virions, resulting in defective viral particles that cannot infect host cells (Nagashunmugam et al., 1997) (Table).

Adaptive immunity and HIV
The effectiveness of adaptive immunity in extinguishing the virus has been more unpredictable (Smith and Wahl, 2005). Protective antibody and cellular responses have been shown in studies of infection-resistant individuals, and alloimmunity has also been speculated to contribute to specific-protective responses against HIV, as may occur in female sex workers, in health workers with multiple exposures, and in vertical transmission (Lehner, 2003). HLA antigens are expressed on CD4+ T-cells, macrophages, neutrophils, and epithelial cells in seminal fluid (Quayle et al., 1997), and repeated exposures may lead to a mucosal allo-immunization. In this regard, in cohorts of HIV-uninfected CCR5+ men and women repeatedly exposed to HIV through sexual intercourse, resistance to infection was associated with anti-gp-160 IgA antibodies in urogenital tract secretions (Mazzoli et al., 1997; Beyrer et al., 1999; Kaul et al., 1999). Many IgA1 samples obtained from serum, saliva, and cervico-vaginal lavage of infection-resistant Kenyan sex workers (Devito et al., 2002) neutralized HIV infection of peripheral blood mononuclear cells (PBMC) in vitro. Furthermore, virus-specific CD8+ T-cell responses have been detected in exposed, but not infected, individuals (Kaul et al., 2001). More effective engagement of humoral and cellular components of the adaptive immune system are pivotal in generating viral resistance at the mucosal surface and in the mucosal-associated lymphoid tissues.

	Antiviral Mechanisms in the Oral Cavity

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
Transmission of HIV in the oral cavity
The oral cavity is considered a relatively protected mucosal site, and orogenital transmission has a very low per-contact risk of acquiring infection, with estimates that 4/10,000 contacts result in infection, and 95% confidence estimates for null rates of infection in association with heterosexual or homosexual oral contact (Vittinghoff et al., 1999; del Romero et al., 2002; Page-Shafer et al., 2002). Vertical transmission from mother to infant during breastfeeding also has a low incidence, but does occur (Scarlatti, 2004). The differences in maturation of the mucosal system in neonates may contribute to susceptibility via this route. In both of these modes of transmission, large volumes of potential viral inoculum may overwhelm the natural protective mechanisms. Nonetheless, this low estimated rate of oral transmission has been hypothesized to be associated with the protective role of the mucosa and salivary constituents in the oral cavity. The presence of unique anti-HIV molecules in saliva, as well as higher concentrations of common antimicrobial and antiretroviral factors, may account for the fact that infectious virus is rarely present in saliva (Shugars and Wahl, 1998; Greenwell-Wild et al., 2006).

Mechanisms of action of salivary viral inhibitors
The relative potencies of the salivary viral inhibitors have not been determined, although their mechanisms of action seem, in many cases, to be complementary. HIV-specific antibodies may bind and, in some instances, neutralize the virus and recruit specific immune responses for clearance. Acidic proline-rich proteins (PRPs), thrombospondin, polyanionic proteins (e.g., albumins), lactoferrin, mucins, and salivary agglutinins, some of which are specific and/or elevated in the oral cavity, reportedly block cell binding and fusion through interactions with gp120 (Table). Defensins appear to inhibit HIV infection at a step prior to reverse-transcription (Table), whereas cystatins may interfere with proteolytic viral processing in the late stages of the viral life cycle (Challacombe and Sweet, 2002). Lactoperoxidase and lysozyme, also found in saliva, demonstrate general antimicrobial activity and have also been shown to have activity against HIV (Shugars and Wahl, 1998). Additionally, non-specific mechanisms, such as lysis of infected cells by the hypotonicity of saliva, may supplement the actions of these inhibitors (Shugars and Wahl, 1998). One of the endogenous antiretroviral agents, which has received considerable attention and has been identified at high levels in saliva, is secretory leukocyte protease inhibitor (SLPI), a potential therapeutic agent.

	Secretory Leukocyte Protease Inhibitor (SLPI)

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
SLPI is a 12-kDa protein, originally identified as a serine protease inhibitor (Fritz, 1988), found in mucosal secretions, including saliva, breast milk, seminal fluid, and other mucosal secretions, which originates from acinar cells of submucosal glands and from epithelial cells lining mucosal surfaces. Nearly a decade ago, SLPI was demonstrated to inhibit HIV infection of human macrophages in vitro (McNeely et al., 1995, 1997; Wahl et al., 1997). Antiviral activity was also demonstrated ex vivo in the secretions of both parotid and submandibular glands (Wahl et al., 1997), and concentrations of SLPI in salivary secretions (0.1–10 µg/mL) were shown to be sufficient to inhibit HIV infection of target macrophages effectively, at least in culture. Further, the acid stability of SLPI ensures its function in the oral environment, and SLPI deletion from whole saliva was shown to result in reduced antiviral activity (McNeely et al., 1995).

In the study comparing innate and adaptive mediators that might influence the levels of HIV RNA and infectious virus in systemic and mucosal compartments, SLPI was found to be inversely correlated with infectious virus levels (Greenwell-Wild et al., 2006), in that the levels of SLPI were highest in the oral cavity, where infectious virus could not be identified, less in the genital mucosa, and least in the peripheral blood, where cultivable HIV was maximal. By comparison, levels of thrombospondin, another HIV-1 inhibitor produced in salivary glands and found in oral secretions, were not associated with viral burden. Neither were antibodies against HIV, as measured by ELISA, consistent with control of virus, since levels of specific IgG and IgA were highest in the blood, where HIV RNA and cultivable virus were both maximal (Greenwell-Wild et al., 2006). These observations prompted exploration of the potential mechanism by which SLPI could exert an antiviral influence in mucosal sites, particularly the oral cavity.

Mechanism of action of SLPI
The mechanism through which SLPI exerts its antiviral action was previously shown to involve a host cell molecule and not the virus itself, and to occur early in the viral life cycle, as confirmed by nested PCR for nascent viral DNA in cells exposed to HIV in the presence of SLPI (McNeely et al., 1995). After considerable effort, an SLPI membrane-binding protein/receptor has recently been identified and demonstrated to play a role in HIV infection (Ma et al., 2004). Multiple complementary approaches—including immuno-precipitation, mass spectroscopy, peptide sequencing, and binding specificity—were used to demonstrate that the phospholipid-binding protein, annexin II, represents a novel macrophage membrane-binding protein for SLPI. More importantly, inhibitors of annexin II were able to block HIV infection of human macrophages in vitro, and to mimic the kinetics of HIV suppression by SLPI. The mechanism of HIV inhibition by SLPI may be explained, at least in part, by the binding affinity of annexin II to phosphatidylserine (PS). PS is a plasma membrane phospholipid acquired by the virus from its host cell during budding (Callahan et al., 2003), and its interaction with annexin II on its next host cell may facilitate viral binding and/or entry. This pathway is consistent with persistent evidence favoring the existence of additional cofactors for binding/entry of HIV, including components of the host cell membrane acquired during viral budding (Freed and Martin, 2001). The SLPI-annexin II connection may be particularly important in interrupting infection of annexin II+ macrophage targets, which are most prominent in later stage AIDS, during opportunistic co-infections, and as reservoirs of HAART-resistant virus (Wahl et al., 2000), and less effective in blocking infection of CD4+ T-cells, deficient in annexin II.

	Conclusions

TOP Abstract Introduction Mucosal Susceptibility: HIV... Differential Protection at... Antiviral Mechanisms in the... Secretory Leukocyte Protease... Conclusions References

 
As exploration in the area of mucosal immunity advances, insight into the mechanisms implemented by HIV during mucosal transmission continues to reveal clues regarding potential strategies to inhibit this devastating infection. The natural protective mechanisms present at mucosal sites, although often effective, are insufficient to ward off repeated exposures and/or bolus inoculation of virus, particularly if the mucosal integrity has been breached. The exceptions of exposed, but non-infected, individuals and the low incidence of oral transmission may provide insights for recognition and development of the most valuable candidate molecules/strategies for therapy and vaccine design. Moreover, understanding the protective mechanisms manipulated or evaded by the virus may be crucial in dissecting disease pathogenesis and combating it.

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