|
Sign In to gain access to subscriptions and/or personal tools.
|
Adv Dent Res 19:21-28, April, 2006
© 2006 SAGE Publications
Innate and Adaptive Mucosal Immunity in Protection against HIV Infection
Presented at the Fifth World Workshop on Oral Health and Disease in AIDS, Phuket, Thailand, July 6–9, 2004, sponsored by Prince of Songkla University, Thailand, the International Association for Dental Research, the World Health Organization, the NIDCR/National Institutes of Health, USA, and the University of California-San Francisco Oral AIDS Center.
L.A. Bergmeier* and
T. Lehner
Mucosal Immunology Unit, Guy’s King’s and St Thomas’ Medical and Dental School, Kings College London, London SE1 9RT, UK
Correspondence: * corresponding author, lesley.bergmeier{at}kcl.ac.uk
 |
Abstract
|
|---|
The appalling toll on the populations of developing countries as a result of the HIV epidemic shows no signs of abatement. While costly drug therapies are effective in developed nations, the sheer scale of the epidemic elsewhere makes the need for a vaccine an ever more urgent goal. The prevalent DNA prime-viral boost strategy aims to elicit cytotoxic lymphocytes (CTL) against HIV, but this approach is undermined by the rapid mutation of HIV, which thereby escapes CTL control. Alloimmunity has been found to be protective in vertical transmission from infected mothers to their babies, in alloimmunization of women with their partners’ mononuclear cells, and in monkeys immunized with SIV grown in human T-cells. Vaginal mucosal immunization, as a result of unprotected sex with a regular partner, induced in vitro protection against HIV infection, and this was confirmed in macaques. The second type of natural protection is found in persons with the homozygous  32 CCR5 mutation, a 32-base-pair deletion of the CCR5 gene, which results in a lack of cell-surface expression of CCR5, which is associated with an increase in CC chemokines and the development of CCR5 antibodies. These two ‘experiments of nature’ have been used to develop vaccine strategies—first, in vaginal immunization of macaques with CCR5 peptides, in addition to HIV envelope (env) and SIV core (gag) antigens, all of which were linked to the 70-kD heat-shock protein (HSP70); and second, in mucosal allo-immunization of macaques, which also gave rise to in vitro protection from infection. Immunization with this vaccine elicited serum and vaginal IgG and IgA antibodies, IFN - and IL-12-producing cells, and increased concentrations of CCL-3 and CCL-4. Vaginal challenge with a simian immunodeficiency virus engineered to carry a human envelope protein (SHIV 89.6) showed significant clearance of SHIV in the immunized macaques. This platform strategy will now be developed to activate the co-stimulatory pathways with the aim of enhancing the primary allogeneic and CCR5-directed responses which are involved in natural protection against HIV infection. Abbreviations: IFN-, gamma interferon; IL-12, interleukin 12; MIP-1  ,β, Macrophage inflammatory protein-1; RANTES, Regulated on activation normal T-cell expressed and secreted; SDF-1, stromal-derived factor 1; SIV, simian immunodeficiency virus; and SHIV, engineered SIV carrying a human envelope protein.
Key Words: HIV • SIV • vaccine • CCR5 • mucosal immunity • alloimmunity
|
Introduction
|
|---|
The HIV pandemic has claimed over 40 million lives (UNAIDS, 2001), and while chemotherapy has had an impact in developed countries, the prohibitive cost of these drugs has limited their use in the developing world. Drug therapy has serious side-effects, and the potential for the emergence of drug-resistant strains of HIV is a major concern. The spread of HIV throughout the developing world poses unprecedented challenges in both the scientific and political arena. The provision of safe drinking water and sanitation, along with vaccination programs, has had a huge impact on the spread of infectious diseases. Vaccines remain the most cost-effective strategies in alleviating the economic and sociological burden of many diseases. The challenge which HIV presents is to develop a vaccine against a chronic infection which has evolved to ‘hijack’ the immune system and result in its ultimate destruction. The difficulties involved in the development of vaccine against chronic viral infection have recently been reviewed (Berzofsky et al. 2001, 2004).
In sub-Saharan Africa, the worst-affected area of the world, the greater number of infections occurs through sexual intercourse, while in the UK more than 50% of new infections are transmitted through heterosexual contact, with women at greater risk of infection than ever before (WHO, 2002).
HIV uses cell-surface receptors to gain entry into the T-cells in which it propagates. CD4 is the main receptor, and a chemokine receptor-CCR5 is the co-receptor utilized by macrophage or M-tropic viruses (sometimes referred to as R5 viruses). CXCR4, an alternative chemokine receptor, is used by viruses later in AIDS infections. These viruses are known as T-tropic or X4 viruses. The distribution of these receptors is critical for the transmission of HIV.
More than 85% of HIV infections are acquired by mucosal transmission. It is therefore essential that vaccine strategies include methodologies which will address three levels of infection with corresponding levels of immunity: (1) immunity at the mucosal sites of transmission, to prevent the virus gaining entry to the immune cells in which it must propagate (Miller et al., 1992; Lehner et al., 1999a; Stevceva and Strober, 2004); (2) regional lymph node immunity—virus has been found in lymph nodes draining the rectal and genital mucosa within hours of exposure at these portals of entry (Spira et al., 1996); and (3) immunity in the systemic circulation. Interruption of the dissemination of virus might prevent the establishment of viral reservoirs. This rationale takes into account the migration pattern of mucosal lymphocytes (Brandtzaeg et al., 1999; Kantele et al., 1999). It is also becoming clear that a successful vaccine must induce not only cytotoxic cells (CTL) to handle cell-associated virus, but also an antibody component to neutralize cell-free viral particles.
To date, three types of vaccine have been evaluated as preventive immunization strategies: (a) DNA vaccination, (b) expression of HIV genes in viral vectors, and (c) combined DNA prime-HIV-carrying viral vector boost (Amara et al., 2001; Crotty et al., 2001). The many studies in animals which have informed these choices are reviewed by Bourinbaiar et al.(2003) and Stevceva and Strober (2004).
The error-prone mechanism of reverse transcription allows for the mutation of HIV and SIV and, as a result, creates serious problems in terms of the virus escaping from control by cytotoxic lymphocytes (Barouch et al., 2002). Numerous vaccines in pre-clinical experiments in macaques and in phase I/II clinical trials have been based on the induction of cytotoxic lymphocytes (CTL). In HIV-infected patients, CD4 and CD8 T-cell responses showed no protective correlation with the plasma viral load (Betts et al., 2001). Recent reports of superinfection of closely related viral strains may also allow for escape from CTL control, which may have been successful in controlling the first virus (Altfeld et al., 2002; Jost et al., 2002; Ramos et al., 2002).
It has been equally difficult to induce neutralizing antibodies which have cross-clade activities. There has also been some concern that antibodies may enhance HIV infectivity (Fust, 1997). However, in experiments with non-human primates, administration of subinfectious doses of SIV in the presence of non-neutralizing antibody did not result in enhancement (Polyanskaya et al., 2001). Mucosal antibodies, and especially secretory IgA, play an important role in protection against HIV infection (reviewed by Kozlowski and Neutra, 2003). Indeed, in previous protection studies in macaques, we were able to demonstrate that the presence of IgA-secreting cells in the iliac lymph nodes of macaques correlated with protection (Bergmeier et al., 1998, 2002).
These difficulties have encouraged a re-examination of areas of vaccine development which have been somewhat neglected. Nature relies not on a single mechanism of protection against infection, but rather on numerous complementary and alternative pathways. Our approach was to exploit the following areas of research:
- Targeting the mucosal immune system and the associated regional lymph nodes by a novel mucosal adjuvant.
- Enhancing innate immunity with its rapid protective response to infection that is independent of memory.
- Stimulating broadly based adaptive immune responses, including memory in CD4, CD8, and B-cells.
- Utilizing host antigens in protection against HIV, as manifest by the experiments of nature, namely, the homozygous 32 CCR5 individuals, and allo-immunity in humans.
|
HIV Receptors and Transmission through Mucosal Tissues
|
|---|
HIV can infect through the intact mucosal epithelia in rectal and genital tissues by infecting Langerhans cells located in the stratified epithelia of the vagina and dendritic cells in the rectum. Several alternative receptors to CD4 and CCR5 have been postulated as carrier molecules for HIV (SIV), including galactosyl ceramide (Bhat et al., 1993). Fc receptors, which bind IgG, have the potential to take up immune complexes composed of antibody and virus particles (Takeda et al., 1988), and seminal fluid has been shown to contain such complexes (Wolff et al., 1992). The C-type lectin DC-SIGN, present on dendritic cells (DC), is able to capture HIV in the absence of CD4 and CCR5, and may carry HIV to the regional lymph nodes. Transmission involves interaction between DC-SIGN and envelope gp120 (Geijtenbeek et al., 2000a,b; Hu et al., 2000; Jameson et al., 2002). Virus may then be transported to numerous mucosal T-cells and is able to infect CD4+ T-cells (Granelli-Piperno et al., 1999). Indeed, co-cultured DCs and T-cells support higher levels of HIV replication than do T-cells alone (Cameron et al., 1992). There is considerable evidence that the gut is the primary target of HIV infection (Veazey et al., 1998), while the rectum has also been identified as a significant reservoir of HIV infection. Anti-retroviral treatment seems to have less influence in rectal tissue than in the blood (DiStefano et al., 2001). A recent study on asymptomatic HIV carriers in Thailand demonstrated that these individuals have numerous p24-positive Langerhans cells in the epithelium of the vagina and thus are able to transmit HIV as part of the natural antigen-processing pathway (Bhoopat et al., 2001; Piguet and Blauvelt, 2002). The role of DCs at the virological synapse has recently been reviewed (Piguet and Sattentau, 2004).
The presence of CCR5+ cells in the rectum and vagina, along with CD4+, results in the selective transmission of R5-HIV viruses across the mucosal epithelium (Zaitseva et al., 1997; Patterson et al., 1998). High concentrations of the CXCR4 ligand SDF-1 (CXCL12) are found in genital epithelium, and this may serve to block and down-modulate the CXCR4 receptor, making it unavailable for X4-HIV transmission (Agace et al., 2000).
|
Targeting the Mucosal Immune System
|
|---|
The mucosal-associated lymphoid system (MALT) is well-defined in the gastro-intestinal, respiratory, and nasal tracts, with inductive sites of aggregated lymphoid tissue (such as Peyer’s patches) and effector sites in the respective mucosal tissues (Gowans and Knight, 1964; Mestecky et al., 1994). A corresponding genital- (and possibly rectal-) associated lymphoid system has not been clearly defined, but tracing the migration of T- and B-cells with the PKH-26 dye has revealed that the internal and external iliac lymph nodes may function as inductive sites from which cells migrate to effector sites in the lamina propria of the cervico-vaginal mucosa and rectum (Mitchell et al., 1998). A significant observation was the induction of both local mucosal, as well as systemic T- and B-cell, responses in macaques and mice (Lehner et al., 1992a,b, 1993, 1994a,Lehner et al., b; Belyakov et al., 1998; Eriksson et al., 1999). Indeed, mucosal or paramucosal (targeting the proximity of the regional lymph nodes) immunization induces: (a) mucosal immunity, which is the first line of defense against HIV; (b) immune responses in the regional lymph node, which is the major inductive site; and (c) systemic immunity, which reaches the other parts of the body via the circulation. Macaques have been protected from rectal infection by direct targeting of the iliac lymph nodes (Lehner et al., 1996; Bergmeier et al., 1998).
|
Innate Immunity
|
|---|
The rapid transmission of SIV or HIV through the mucosa to the regional lymph nodes may not allow the cognate, memory-driven immune system to prevent infection. However, the innate immune system allows for the rapid deployment of cells and soluble factors in protection against microbial infection. The large number of Langerhans cells in the vagina, foreskin, and oral epithelium (Hussain and Lehner, 1995),  T-cells in rectal and vaginal epithelium, and macrophages and dendritic cells in the subepithelium enable these cells to secrete numerous chemokines and cytokines that may block HIV transmission and replication in the mucosal tissues. The CC (or β) chemokines may block HIV access to CCR5 co-receptors and may attract the immunological repertoire of cells (T- and B-cells, DC, and macrophages) to the mucosal site. Type I IFN (interferon) and the complement system may play an important role (Lehner, 2002). The concept is that the innate immune system may drive the adaptive immune response and modulate T-cell polarization.
|
CD8-Suppressor Factors and Chemokines
|
|---|
CD8-suppressor factor (SF) or CD8 cell anti-viral factor (CAF) is released from CD8-cells and inhibits HIV replication in CD4+ cells (Walker et al., 1986; Mackewicz and Levy, 1992; Cocchi et al., 1995). The known anti-viral cytokines failed to account for the CD8-SF, and it is now established that several anti-HIV factors are generated by the stimulation of CD8 cells.
The CC chemokines bind to the CCR5 receptors and prevent M-tropic HIV infection and both M- and T-tropic SIV infection (Chen et al., 1997). The T-cell-tropic HIV receptor CXCR4 binds the chemokine CXCL12 (SDF1) and is not involved in SIV infection. Other chemokine co-receptors have been identified, of which Bonzo and Bob bind both HIV1 and SIV (Deng et al., 1996, 1997; Alkhatib et al., 1997; Liao et al., 1997), whereas GPR1 appears to be specific for SIV (Farzan et al., 1997). The chemokines corresponding to these 3 co-receptors have not yet been identified. However, the finding of several co-receptors, and the known switch from M-tropic HIV1-binding CCR5 to T-tropic HIV1-binding CXCR4 with the development of AIDS, suggests that immune pressure and/or increased generation of chemokines may mediate the development of alternative HIV/SIV co-receptor binding viruses.
However, the CC chemokines RANTES, MIP-1, and MIP-1β(CCL 5, 3, and 4) are produced by activation of macrophages, dendritic cells, T-cells, Natural Killer cells, and T-cells bearing the T-cell receptor (Sallusto et al., 1999; Lehner et al., 2000b; Babaahmady et al., 2002). There is a great deal of evidence that the 3 CC chemokines can block the CCR5 co-receptors and prevent HIV infection in vitro (Cocchi et al., 1995) or SIV infection in vivo (Lehner et al., 1996). In vivo, the 3 chemokines were generated specifically by immunization with SIV gp120 and p27 in alum (Lehner et al., 1996; Aubertin et al., 2000), xeno-immunization in macaques (Wang et al., 1998), and allo-immunization in women (Wang et al., 1999a, 2002a). There is also evidence, both in vitro (Aramori et al., 1997) and in vivo (Lehner et al., 2000c), that raised concentrations of CC chemokines down-modulate the cell-surface expression of CCR5.
Resting or activated CD8-enriched cells eluted from normal rectal mucosa generate a large number of CCL 4 and 5 secreting cells (Lehner et al., 2000a). This might be due to stimulation by many Gram-negative and -positive bacteria residing in the rectum, since these contain lipopolysaccharides (LPS) and heat-shock proteins (HSP), both of which induce CC chemokines. Consistent with these findings is the increased concentration of CCL 3, 4, and 5 secreted by iliac compared with axillary lymph node cells (Aubertin et al., 2000), since the former drain the rectal mucosa, with its indigenous microbial population, unlike the axillary lymph nodes, which drain the relatively aseptic skin. Furthermore, the highest mRNA levels of CC chemokines were reported from lymph nodes draining the mucosal tissues (Abel et al., 2001).
Chemokines have been demonstrated in cervico-vaginal washings from HIV-infected women (Patterson et al., 1998), and CCL5 might be protective at the surface of the cervico-vaginal mucosa (Spear et al., 1998).
|
Mucosal Adjuvants
|
|---|
Most vaccines, with the exception of replicating viruses, require an adjuvant to initiate adaptive immunity. CD4+ T-helper cells are induced as part of this response, and the effector molecules and cells have been categorized into a T-helper 1 (Th1) response—associated with IL-2, IFN secretion, and the induction of cytotoxic cells—or a Th2 response, associated with IL-4, IL-10, and antibody production. The best-defined mucosal adjuvant is cholera toxin, which binds GM-1 gangliosides expressed on epithelial cells. E. coli heat-labile toxin (LT) is also a potent mucosal adjuvant and binds GM-1. However, while CT induces predominantly Th2 responses, LT may induce both Th1 and Th2 responses. Microparticles of biodegradable polymers of polylactide-co-glycolides, CpG-DNA, and the incorporation of cytokines or chemokines are also important mucosal adjuvants (Holmgren et al., 2003; Yuki and Kiyono, 2003). The features of mucosal adjuvants and their polarizing effects are listed in the Table .
The objective of mucosal immunization is to elicit mucosal and regional lymph node immune responses to include secretory IgA, IgG, T-cell responses, and enhanced chemokine and cytokine production. The interplay between innate and adaptive immunity requires multiple signals. Signal 1 is dependent on the cognate immunity generated through HLA-peptide and TCR (T-cell receptor). Signal 2 is the co-stimulation which occurs between B7-CD28 (Bretscher, 1999). However, an adequate immune response is usually not invoked unless an appropriate adjuvant, which will induce innate responses, is also present. This can be elicited by a microbial product generating a third signal (or danger signal) (Medzhitov and Janeway, 1997). HSP70 has been shown to engage the CD40 co-stimulatory pathway to produce signal 3 (Wang et al., 2001). The adjuvant function of HSP70 has been well-established (Barrios et al., 1992; Perraut et al., 1993). We have recently demonstrated potent mucosal adjuvanticity by HSP70, which is dependent on stimulating the production of CC chemokines (Lehner et al., 2000a), thereby attracting the monocytes, immature DC, T-cells, and B-cells and driving the adaptive immune response (Kim et al., 1998; Sallusto et al., 2000). Rectal or vaginal mucosal immunization stimulates the production of CCL 3, 4, and 5 and elicits mucosal and systemic IgA and IgG antibodies and T-cell proliferative responses to the antigen linked to HSP70 (Fig. 1; Lehner et al., 2000a). These CC chemokines can block and down-modulate CCR5, which is the main co-receptor of M-tropic HIV. The innate or CC-chemokine-generating component of HSP70 is linked with a specific peptide that resides in the pocket of HSP70 and elicits specific immunity (Fig. 1). HSP70 binds CD40 in stimulating macrophages and DC to generate CC chemokines (Wang et al., 2001) and IL-12 when the c-terminal portion of HSP70 is administered (Wang et al., 2002b). This function, linked with that of HSP70-translocating molecules from outside the cell into the HLA class I pathway, enables HSP70 to elicit cytotoxic cells (CTL) as well as IgG2a antibody responses. This mechanism allows HSP70 to drive a TH1 response.
View larger version (15K):
[in this window]
[in a new window]
|
Fig. 1 - The use of heat-shock proteins as mucosal adjuvants. Antibody and T-cell responses to SIV gp120 and p27 following rectal immunization with SIV antigens covalently linked to HSP60 or 70.
|
|
|
Exploiting the Experiments of Nature
|
|---|
(a) Down-modulation of CCR5 and up-regulation of CC chemokines
The most striking resistance to HIV infection is in the naturally occurring 32 CCR5 mutation in approximately 1% of Caucasians (Dean et al., 1996; Deng et al., 1996). These individuals lack cell-surface expression of CCR5, have increased concentrations of the 3 chemokine ligands [CCL 3, 4, and 5 (Paxton et al., 1996)], and may develop antibodies to CCR5 (Ditzel et al., 1998).
We have developed a simian model of immunization against SIV/HIV infection that attempts to reproduce some of the functional aspects of the 32 CCR5 mutation. The novel vaccine strategy utilizes both the CCR5 co-receptor and HIV/SIV antigens in preventing SHIV transmission. The CCR5 co-receptors can be blocked by the 3 chemokines that down-modulate the cell-surface expression of CCR5 and may elicit protection in vivo (Lehner et al., 1996, 2000a,Lehner et al., b,c; Heeney et al., 1998; Ahmed et al., 1999; Wang et al., 1999b). In a series of experiments using HSP70 as a mucosal adjuvant, we have covalently linked SIV gp120 and p27 and applied the vaccine rectally in macaques. We were able to induce antibody in both serum and rectal washings, and to induce significant T-cell responses to the SIV antigens (Lehner et al., 2000c). Most importantly, however, was the elevated production of the 3 CC chemokines, which are the ligands for CCR5. HSP70 translocates molecules from outside the cell into the HLA class I pathway (Castellino et al., 2000) and acts as a TH1 polarizing agent. However, the increased CC chemokine concentration does not result in the complete blockade of CCR5. In vitro experiments (Lehner et al., 1999b, 2000a) had previously shown that monoclonal antibodies directed at the viral receptors can inhibit viral replication to greater than 90% with antibodies to CCR5 (Fig. 2). This finding has been exploited by immunizing macaques with CCR5. B- and T-cell epitope mapping indicated that the most immunogenic area of this seven-transmembrane protein can be represented by 3 extracellular peptides, namely, the N terminal residues 1–20, and the first loop and the second peptide of the second loop. These 3 peptides have become part of our vaccine strategy. We were able to show a synergistic effect of combining antibodies to CCR5 with the natural chemokine ligands in inhibiting the replication of HIV in vitro (Lehner et al., 2001). These CCR5 antibodies are found not only in individuals with the 32 CCR5 mutation, but also in xeno-immunized macaques (Heeney et al., 1998), allo-immunized humans (Wang et al., 1999a, 2002a), seronegative women at risk of HIV infection (Lopalco et al., 2000), and in DNA-immunized macaques (Zuber et al., 2000).
View larger version (15K):
[in this window]
[in a new window]
|
Fig. 2 - The effects of monoclonal antibodies on SIV replication in vitro. Antibodies to cell-surface molecules inhibit replication of virus.
|
|
This novel vaccine strategy has recently been utilized in a challenge experiment in which groups of macaques were immunized with a vaccine consisting of the 3 extracellular CCR5 peptides, an N-terminal fragment of HIV gp120 generated in plants, and recombinant SIV p27. These were covalently linked to HSP70 as a mucosal adjuvant and administered either via the vaginal mucosa or by targeting the proximity of the draining iliac lymph nodes (Bogers et al., 2004a). The animals were challenged by inoculation into the vagina one month following the final immunization. Serum and vaginal fluid IgG and IgA, IL-2- and IFN-producing cells, and the CC chemokines CCL3 and 4 (MIP 1β and MIP 1) were significantly raised in immunized macaques (P = 0.01–0.05). Vaginal challenge with SHIV89.6P infected all macaques, but sequential analysis over 24 wks showed a significant variation in viral loads between animals (P = 0.05). Whereas SHIV89.6P persisted in 4 unimmunized macaques, in 5 out of 8 immunized macaques the virus was cleared or became undetectable by reverse transcriptase-polymerase chain-reaction (RT-PCR) (Fig. 3). The CD4 counts in the immunized macaques were significantly higher than those in unimmunized animals (P < 0.05). Similar results were found in macaques immunized with a CCR5-SIV combined vaccine and challenged intravenously with SIVmac 8980 (Bogers et al., 2004b).
View larger version (18K):
[in this window]
[in a new window]
|
Fig. 3 - Targeting the mucosal effector sites with a SHIV vaccine incorporating HIV env, SIV gag, and the 3 CCR5 peptides. Viral loads after vaginal challenge in animals vaccinated via the vaginal compared with TLN (Targeted Iliac Lymph node) immunization.
|
|
We concluded that an immunization strategy that targets both the virus and its CCR5 receptor has significantly inhibited SHIV89.6P and SIV 8980, and may serve as a novel strategy in the prevention of HIV transmission (Fig. 4).
View larger version (14K):
[in this window]
[in a new window]
|
Fig. 4 - Dual-protection hypothesis against HIV/SIV. Cognate immunity against HIV/SIV or CCR5 (1 and 3) and innate immunity (2) by CC-chemokines blocking or down-modulating CCR5 (from Lehner et al., 1999a).
|
|
(b) Alloimmunity—a role in protection against HIV
Sexually transmitted diseases in general, and HIV infection in particular, are transmitted through the vaginal or rectal mucosa. A potentially important factor which has not been explored in the past is the effect of HLA antigens in the cells found in ejaculates on the immune response of the partner. Ejaculates contain CD4-positive T-cells, macrophages, neutrophils, immature germ cells (Quayle et al., 1997), epithelial cells that express HLA antigens (Koelman et al., 2000), and cell-free HLA antigens. Spermatozoa may express HLA class I and II antigens, though in a cyclical pattern (Martin-Villa et al., 1999). The possibility that HLA antigens in ejaculates might elicit an allo-immune response needs to be studied, especially since systemic allo-immunization induces one of the most potent natural immune responses, in which up to 10% of the T-cell repertoire is directed against HLA antigens (Suchin et al., 2001; Blattman et al., 2002).
To the best of our knowledge, there is no recorded evidence that mucosal allo-immunity has been investigated. This is somewhat surprising, in view of the common exposure of vaginal or rectal mucosa to allo-antigens in ejaculates. However, we have recently reported that unprotected sexual intercourse with a monogamous partner elicits a significant allo-immune response to the partner’s mononuclear cells, compared with unrelated cells (Peters et al., 2004). The CD4+ T-cells from these women showed significant in vitro resistance to HIV-1 infection, compared with cells from those who practiced protected sex.
Xeno-immunization of macaques with SIV grown in human T-cells has consistently protected the animals from SIV infection (Desrosiers et al., 1989; Murphey-Corb et al., 1989; Carlson et al., 1990; Stott et al., 1990; Langlois et al., 1992). There is also evidence that allo-immunization in macaques may protect them against SIV infection (Stott, 1994).
Indeed, antibodies to cell-surface antigens such as classes I and II were found in the sera of protected macaques (Bergmeier et al., 1994). Furthermore, we have been able to demonstrate that antibodies to Classes I and II and CCR5 are able to inhibit replication of SIV (Fig. 2 ; Lehner et al., 1999b). Animals infected with SIV grown in macaque cells have species-specific antibodies to these antigens (Polyanskaya et al., 2003). Xeno-immunization of macaques significantly increased the concentration of CD8-derived suppressor factor (SF), CCL-5, CCL-3, and CCL-4 (RANTES, MIP-1, and MIP-1β), which were associated with protection against SIV infection (Wang et al., 1998). Furthermore, human in vitro studies suggest that allo-antigens may induce HIV cross-reactive antibodies, cytotoxic lymphocytes, or soluble factors (Clerici et al., 1993; Shearer et al., 1993; Bruhl et al., 1996). Systemic allo-immunization in women revealed that the 3 CC chemokines are significantly up-regulated, and the CCR5 and CXCR4 co-receptors are down-modulated (Wang et al., 2002a). Both M-and T-tropic HIV replication was inhibited in vitro by CD8-SF derived from peripheral blood mononuclear cells (PBMC) of these women, in addition to a dose-dependent decrease in infectivity of CD4+ T-cells. Indeed, it has been suggested that successful veterinary vaccines are dependent on allo-responses (reviewed by Bourinbaiar et al., 2003).
Allo-immunization has been proposed as a strategy for inducing immune protection against HIV infection (Shearer et al., 1993; Lehner et al., 2000d). Epidemiological evidence suggests that sex workers in West Africa who appear to be resistant to HIV infection express rare HLA alleles (Celum et al., 1994). Transmission of HIV from mother to baby occurs more frequently among uniparous women (Kind, 1995), and mother-child HLA-class I concordance increases perinatal HIV-1 transmission (MacDonald et al., 1998). Furthermore, selected sera from multiparous women showed significant CCR5 antibodies and in vitro inhibition of HIV-1 replication (Wang et al., 1999a). On the basis of these findings, we postulated the hypothesis that vaginal or rectal exposure to HLA antigens in ejaculates might elicit mucosal allo-immunity, generating CD8 cell-derived anti-viral factors and CC chemokines that affect immunity and transmission of the R5 strains of HIV.
In preliminary experiments in macaques, we have applied irradiated autologous or allogeneic cells to either the rectum or the vagina and measured the level of response by the mixed-lymphocyte reaction. The level of CC chemokine production induced was also measured. Autologous cells did not induce a mixed-lymphocyte reaction (MLR) or any increase in the level of CC chemokines, but both of these were elevated in animals exposed to allo-immunization. CD8-suppressor factor (CD8-SF) was also elevated, and the T-cells of allostimulated animals were more intransigent to SIV infection (Bergmeier et al., 2005).
Taken together, these preliminary experiments are proof, in principle, that allo-immunization may be highly efficacious in protecting individuals from HIV infection (Fig. 5).
|
Summary
|
|---|
There is a pressing need for an HIV vaccine, but despite valiant efforts over many years, conventional approaches using viral antigens or DNA have not brought us any closer to controlling AIDS through vaccination. The approach we have taken is to utilize the innate immune system, coupled with the mucosal immune response, to generate effector mechanisms at the mucosal site of infection. We have been encouraged by the results we have obtained in trying to mimic the experiments of nature by blocking and down-modulating the main co-receptor of the R5 virus, and by the induction of alloresponses with the concomitant up-regulation of the innate factors that are able to inhibit viral replication.
|
References
|
|---|
- Abel K, Alegria-Hartman MJ, Zanotto K, McChesney MB, Marthas ML, Miller CJ (2001). Anatomic site and immune function correlate with relative cytokine mRNA expression levels in lymphoid tissues of normal rhesus macaques. Cytokine 16:191–204.[CrossRef][Medline]
[Order article via Infotrieve]
- Agace WW, Amara A, Roberts AI, Pablos JL, Thelen S, Uguccioni M, et al. (2000). Constitutive expression of stromal derived factor-1 by mucosal epithelia and its role in HIV transmission and propagation. Curr Biol 10:325–328.[CrossRef][Medline]
[Order article via Infotrieve]
- Ahmed RK, Nilsson C, Wang Y, Lehner T, Biberfeld G, Thorstensson R (1999). Beta-chemokine production in macaques vaccinated with live attenuated virus correlates with protection against simian immunodeficiency virus (SIVsm) challenge. J Gen Virol 80:1569–1574.[Abstract]
- Alkhatib G, Liao F, Berger EA, Farber JM, Peden KW (1997). A new SIV co-receptor STRL33. Nature 388:238.[CrossRef][Medline]
[Order article via Infotrieve]
- Altfeld M, Allen TM, Yu XG, Johnston MN, Agrawal D, Korber BT, et al. (2002). HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature 420:434–439.[CrossRef][Medline]
[Order article via Infotrieve]
- Amara RR, Villinger F, Altman JD, Lydy SL, O’Neil SP, Staprans SI, et al. (2001). Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 292:69–74.[Abstract/Free Full Text]
- Aramori I, Ferguson SS, Bieniasz PD, Zhang J, Cullen B, Cullen MG (1997). Molecular mechanism of desensitization of the chemokine receptor CCR-5: receptor signaling and internalization are dissociable from its role as an HIV-1 co-receptor. EMBO J 16:4606–4616.[CrossRef][Medline]
[Order article via Infotrieve]
- Aubertin AM, Le Grand R, Wang Y, Beyer C, Tao L, Neildez O, et al. (2000). Generation of CD8+ T cell-generated suppressor factor and beta chemokines by targeted iliac lymph node immunization in rhesus monkeys challenged with SHIV-89.6P by the rectal route. AIDS Res Hum Retroviruses 16:381–392.[CrossRef][Medline]
[Order article via Infotrieve]
- Babaahmady K, Bergmeier LA, Whittall T, Singh M, Wang Y, Lehner T (2002). A comparative investigation of CC chemokines and SIV suppressor factors generated by CD8+ and CD4+ T cells and CD14+ monocytes. J Immunol Methods 264:1–10.[CrossRef][Medline]
[Order article via Infotrieve]
- Barouch DH, Kunstman J, Kuroda MJ, Schmitz JE, Santra S, Peyerl FW, et al. (2002). Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 415:335–339.[CrossRef][Medline]
[Order article via Infotrieve]
- Barrios C, Lussow AR, Van Embden J, Van der Zee R, Rappuoli R, Costantino P, et al. (1992). Mycobacterial heat-shock proteins as carrier molecules. II: The use of the 70-kDa mycobacterial heat-shock protein as carrier for conjugated vaccines can circumvent the need for adjuvants and Bacillus Calmette Guerin priming. Eur J Immunol 22:1365–1372.[Medline]
[Order article via Infotrieve]
- Belyakov IM, Ahlers JD, Brandwein BY, Earl P, Kelsall BL, Moss B, et al. (1998). The importance of local mucosal HIV-specific CD8(+) cytotoxic T lymphocytes for resistance to mucosal viral transmission in mice and enhancement of resistance by local administration of IL-12. J Clin Invest 102:2072–2081.[Medline]
[Order article via Infotrieve]
- Bergmeier LA, Walker J, Tao L, Cranage M, Lehner T (1994). Antibodies to human and non-human primate cellular and culture medium components in macaques vaccinated with the simian immunodeficiency virus. Immunology 83:213–220.[Medline]
[Order article via Infotrieve]
- Bergmeier LA, Mitchell EA, Hall G, Cranage MP, Cook N, Dennis M, et al. (1998). Antibody secreting cells specific for simian immunodeficiency virus antigens in lymphoid and mucosal tissues of immunized macaques. AIDS 12:1139–1147.[Medline]
[Order article via Infotrieve]
- Bergmeier LA, Wang Y, Lehner T (2002). The role of immunity in protection from mucosal SIV infection in macaques. Oral Dis 8(Suppl 2):63–68.[CrossRef][Medline]
[Order article via Infotrieve]
- Bergmeier LA, Babaahmady K, Wang Y, Lehner T (2005). Mucosal alloimmunization elicits T-cell proliferation, CC chemokines, CCR5 antibodies and inhibition of simian immunodeficiency virus infectivity. J Gen Virol 86:2231–2238.[Abstract/Free Full Text]
- Berzofsky JA, Ahlers JD, Belyakov IM (2001). Strategies for designing and optimising new generation vaccines. Nat Rev Immunol 1:209–219.[CrossRef][Medline]
[Order article via Infotrieve]
- Berzofsky JA, Ahlers JD, Janik J, Morris J, Oh S, Terabe M, et al. (2004). Progress on new vaccine strategies against chronic viral infections. J Clin Invest 114:450–462.[CrossRef][Medline]
[Order article via Infotrieve]
- Betts MR, Ambrozak DR, Douek DC, Bonhoeffer S, Brenchley JM, Casazza JP, et al. (2001). Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol 75:11983–11991.[Abstract/Free Full Text]
- Bhat S, Mettus RV, Reddy EP, Ugen KE, Srikanthan V, Williams WV, et al. (1993). The galactosyl ceramide/sulfatide receptor binding region of HIV-1 gp120 maps to amino acids 206–275. AIDS Res Hum Retroviruses 9:175–181.[Medline]
[Order article via Infotrieve]
- Bhoopat L, Eiangleng L, Rugpao S, Frankel SS, Weissman D, Lekawanvijit S, et al. (2001). In vivo identification of Langerhans and related dendritic cells infected with HIV-1 subtype E in vaginal mucosa of asymptomatic patients. Mod Pathol 14:1263–1269.[CrossRef]
- Blattman JN, Antia R, Sourdive DJ, Wang X, Kaech SM, Murali-Krishna K, et al. (2002). Estimating the precursor frequency of naïve antigen-specific CD8 T cells. J Exp Med 195:657–664.[Abstract/Free Full Text]
- Bogers WM, Bergmeier LA, Ma J, Oostermeijer H, Wang Y, Kelly CG, et al. (2004a). A novel HIV-CCR5 receptor vaccine strategy in the control of mucosal SIV/HIV infection. AIDS 18:25–36.[CrossRef][Medline]
[Order article via Infotrieve]
- Bogers WM, Bergmeier LA, Oostermeijer H, ten Haaft P, Wang Y, Kelly CG, et al. (2004b). CCR5 targeted SIV vaccination strategy preventing or inhibiting SIV infection. Vaccine 22:2974–2984.[CrossRef][Medline]
[Order article via Infotrieve]
- Bourinbaiar AS, Metadilogkul O, Jirathitikal V (2003). Mucosal AIDS vaccines. Viral Immunol 16:427–445.[Medline]
[Order article via Infotrieve]
- Brandtzaeg P, Farstad IN, Haraldsen G (1999). Regional specialization in the mucosal immune system: primed cells do not always home along the same track. Immunol Today 20:267–277.[CrossRef][Medline]
[Order article via Infotrieve]
- Bretscher PA (1999). A two step, two-signal model for the primary activation of precursor helper T cells. Proc Natl Acad Sci USA 96:185–190.[Abstract/Free Full Text]
- Bruhl P, Kerschbaum A, Zimmermann K, Eibl MM, Mannhalter JW (1996). Allostimulated lymphocytes inhibit replication of HIV type 1. AIDS Res Hum Retroviruses 12:31–37.[Medline]
[Order article via Infotrieve]
- Carlson JR, McGraw TP, Keddie E, Yee JL, Rosenthal A, Langlois AJ, et al. (1990). Vaccine protection of rhesus macaques against simian immunodeficiency virus infection. AIDS Res Hum Retroviruses 6:1239–1246.[Medline]
[Order article via Infotrieve]
- Cameron PU, Freudenthal PS, Barker JM, Gezelter S, Inaba K, Steinman RM (1992). Dendritic cells exposed to human immunodeficiency virus type -1 transmit a vigorous cytopathic infection to CD4+ T cells. Science 257:383–387.[Abstract/Free Full Text]
- Castellino F, Boucher PE, Eichelberg K, Mayhew M, Rothman JE, Houghton AN, et al. (2000). Receptor-mediated uptake of antigen/heat shock protein complexes results in major histocompatibility complex class I antigen presentation via two distinct processing pathways. J Exp Med 191:1957–1964.[CrossRef][Medline]
[Order article via Infotrieve]
- Celum CL, Coombs RW, Jones M, Murphy V, Fisher L, Grant C, et al. (1994). Risk factors for repeatedly reactive HIV-1 EIA and indeterminate Western blots. A population based case-control study. Arch Intern Med 154:1129–1137.[Abstract/Free Full Text]
- Chen Z, Zhou P, Ho DD, Landau NR, Marx PA (1997). Genetically divergent strains of simian immunodeficiency virus use CCR5 as a coreceptor for entry. J Virol 71:2705–2714.[Abstract]
- Clerici M, Shearer G, Hounsell EF, Jameson B, Habeshaw J, Dalgleish AG (1993). Alloactivated cytotoxic T cells recognize the carboxy-terminal domain of human immunodeficiency virus-1 gp120 envelope glycoprotein. Eur J Immunol 23:2022–2025.[Medline]
[Order article via Infotrieve]
- Cocchi F, DeVico AL, Garzino-Demo A, Arya SK, Gallo RC, Lusso P (1995). Identification of RANTES, MIP-1 alpha and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811–1815.[Abstract/Free Full Text]
- Crotty S, Miller CJ, Lohman BL, Neagu MR, Compton L, Lu D, et al. (2001). Protection against simian immunodeficiency virus vaginal challenge by using Sabin poliovirus vectors. J Virol 75:7435–7452.[Abstract/Free Full Text]
- Dean M, Carrington M, Winkler C, Huttley GA, Smith MW, Allikmets R, et al. (1996). Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study. Science 273:1856–1862.[Abstract/Free Full Text]
- Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, et al. (1996). Identification of a major co-receptor for primary isolates of HIV-1. Nature 381:661–666.[CrossRef][Medline]
[Order article via Infotrieve]
- Deng HK, Unutmaz D, KewalRamani VN, Littman DR (1997). Expression cloning of new receptors used by simian and human immunodeficiency viruses. Nature 388:296–300.[CrossRef][Medline]
[Order article via Infotrieve]
- Desrosiers RC, Wyand MS, Kodama T, Ringler DJ, Arthur LO, Sehgal PK, et al. (1989). Vaccine protection against simian immunodeficiency virus infection. Proc Natl Acad Sci USA 86:6353–6357.[Abstract/Free Full Text]
- Di Stefano M, Favia A, Monno L, Lopalco P, Caputi O, Scardigno AC, et al. (2001). Intracellular and cell-free (infectious) HIV-1 in rectal mucosa. J Med Virol 65:637–643.[Medline]
[Order article via Infotrieve]
- Ditzel HJ, Rosenkilde MM, Garred P, Wang M, Koefoed K, Pedersen C, et al. (1998). The CCR5 receptor acts as an alloantigen in CCR5delta32 homozygous individuals: identification of chemokine and HIV-1-blocking human antibodies. Proc Natl Acad Sci USA 95:5241–5245.[Abstract/Free Full Text]
- Eriksson K, Quiding-Jarbrink M, Osek J, Nordstrom I, Hjulstrom M, Holmgren J, et al. (1999). Anatomic segmentation of the intestinal immune response in nonhuman primates: differential distribution of B cells after oral and rectal immunizations to sites defined by their source of vascularization. Infect Immun 67:6210–6212.[Abstract/Free Full Text]
- Farzan M, Choe H, Martin K, Marcon L, Hofmann W, Karlsson G, et al. (1997). Two orphan seven-transmembrane segment receptors which are expressed in CD4-positive cells support simian immunodeficiency virus infection. J Exp Med 186:405–411.[Abstract/Free Full Text]
- Fust G (1997). Enhancing antibodies in HIV infection. Parasitology 115(Suppl):S127–S140.
- Geijtenbeek TB, Torensma R, van Vliet SJ, van Duijnhoven GC, Adema GJ, van Kooyk Y, et al. (2000a). Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell 100:575–585.[CrossRef][Medline]
[Order article via Infotrieve]
- Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, et al. (2000b). DC-SIGN, a dendritic cell-specific HIV-1 binding protein that enhances trans-infection of T cells. Cell 100:587–597.[CrossRef][Medline]
[Order article via Infotrieve]
- Gowans JL, Knight EJ (1964). The route of re-circulation of lymphocytes in the rat. Proc R Soc Lond B Biol Sci 159:257–282.[Medline]
[Order article via Infotrieve]
- Granelli-Piperno A, Finkel V, Delgado E, Steinman RM (1999). Virus replication begins in dendritic cells during the transmission of HIV-1 from mature dendritic cells to T cells. Curr Biol 1:21–29.[Medline]
[Order article via Infotrieve]
- Heeney JL, Teeuwsen VJ, van Gils M, Bogers WM, DeGiuli Morghen C, Radaelli A, et al. (1998). beta-chemokines and neutralizing antibody titers correlate with sterilizing immunity generated in HIV-1 vaccinated macaques. Proc Natl Acad Sci USA 95:10803–10808.[Abstract/Free Full Text]
- Holmgren J, Czerkinsky C, Eriksson K, Mharandi A (2003). Mucosal immunisation and adjuvants: a brief overview of recent advances and challenges. Vaccine 21(Suppl 2):S89–S95.[CrossRef][Medline]
[Order article via Infotrieve]
- Hu J, Gardner MB, Miller CJ (2000). Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 74:6087–6095.[Abstract/Free Full Text]
- Hussain LA, Lehner T (1995). Comparative investigation of Langerhans’ cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology 85:475–484.[Medline]
[Order article via Infotrieve]
- Jameson B, Baribaud F, Pohlmann S, Ghavimi D, Mortari F, Doms RW, et al. (2002). Expression of DC-SIGN by dendritic cells of intestinal and genital mucosae in humans and rhesus macaques. J Virol 76:1866–1875.[Abstract/Free Full Text]
- Jost S, Bernard MC, Kaiser L, Yerly S, Hirschel B, Samri A, et al. (2002). A patient with HIV-1 superinfection. N Engl J Med 347:731–736.[Free Full Text]
- Kantele A, Zivny J, Hakkinen M, Elson CO, Mestecky J (1999). Differential homing commitments of antigen-specific T cells after oral or parenteral immunization in humans. J Immunol 162:5173–5177.[Abstract/Free Full Text]
- Kim JJ, Nottingham LK, Sin JI, Tsai A, Morrison L, Oh J, et al. (1998). CD8 positive T cells influence antigen-specific immune responses through the expression of chemokines. J Clin Invest 102:1112–1124.[Medline]
[Order article via Infotrieve]
- Kind C (1995). Mother-to-child transmission of human immunodeficiency virus type 1: influence of parity and mode of delivery. Paediatric AIDS Group of Switzerland. Eur J Pediatr 154:542–545.[CrossRef][Medline]
[Order article via Infotrieve]
- Koelman CA, Coumans AB, Nijman HW, Doxiadis II, Dekker GA, Claas FH (2000). Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid? J Reprod Immunol 46:155–166.[CrossRef][Medline]
[Order article via Infotrieve]
- Kozlowski PA, Neutra MR (2003). The role of mucosal immunity in prevention of HIV transmission. Curr Mol Med 3:217–228.[CrossRef][Medline]
[Order article via Infotrieve]
- Langlois AJ, Weinhold KJ, Matthews TJ, Greenberg ML, Bolognesi DP (1992). The ability of certain SIV vaccines to provoke reactions against normal cells. Science 255:292–293.[Free Full Text]
- Lehner T (2002). Innate immunity in HIV infection. In: AIDS vaccine research. Wong-Staal F, Gallo RC, editors. New York: Marcel Dekker, pp. 261–286.
- Lehner T, Bergmeier LA, Panagiotidi C, Tao L, Brookes R, Klavinskis LS, et al. (1992a). Induction of mucosal and systemic immunity to a recombinant simian immunodeficiency viral protein. Science 258:1365–1369.[Abstract/Free Full Text]
- Lehner T, Panagiotidi C, Bergmeier LA, Tao P, Brookes R, Adams S (1992b). A comparison of the immune responses following oral, vaginal or rectal route of immunization with SIV antigens in non-human primates. Vaccine Res 1:319–330.
- Lehner T, Brookes R, Panagiotidi C, Tao L, Klavinskis LS, Walker J, et al. (1993). T- and B-cell functions and epitope expression in nonhuman primates immunized with simian immunodeficiency virus antigen by the rectal route. Proc Natl Acad Sci USA 90:8638–8642.[Abstract/Free Full Text]
- Lehner T, Tao L, Panagiotidi C, Klavinskis LS, Brookes R, Hussain L, et al. (1994a). Mucosal model of genital immunization in male rhesus macaques with a recombinant simian immunodeficiency virus p27 antigen. J Virol 68:1624–1632.[Abstract/Free Full Text]
- Lehner T, Bergmeier LA, Tao L, Panagiotidi C, Klavinskis LS, Hussain L, et al. (1994b). Targeted lymph node immunization with simian immunodeficiency virus p27 antigen to elicit genital, rectal and urinary immune responses in nonhuman primates. J Immunol 153:1858–1868.[Abstract]
- Lehner T, Wang Y, Cranage M, Bergmeier LA, Mitchell E, Tao L, et al. (1996). Protective mucosal immunity elicited by targeted iliac lymph node immunization with a subunit SIV envelope and core vaccine in macaques. Nat Med 2:767–775.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Bergmeier L, Wang Y, Tao L, Mitchell E (1999a). A rational basis for mucosal vaccination against HIV infection. Immunol Rev 170:183–196.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Wang Y, Doyle C, Tao L, Bergmeier LA, Mitchell E, et al. (1999b). Induction of inhibitory antibodies to CCR5 chemokine receptor and their complementary role in preventing SIV infection in macaques. Eur J Immunol 29:2427–2435.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Bergmeier LA, Wang Y, Tao L, Sing M, Spalleck R, et al. (2000a). Heat shock proteins generate beta chemokines which function as innate adjuvants enhancing adaptive immunity. Eur J Immunol 30:594–603.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Mitchell E, Bergmeier L, Singh M, Spallek R, Cranage M, et al. (2000b). The role of gammadelta T cells in generating antiviral factors and beta chemokines in protection against mucosal simian immunodeficiency virus infection. Eur J Immunol 30:2245–2256.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Wang Y, Cranage M, Tao L, Mitchell E, Bravery C, et al. (2000c). Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in non-human primates. Immunology 99:569–577.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Shearer GM, Hackett CJ, Schultz A, Sharma OK (2000d). Alloimmunization as a strategy for vaccine design against HIV/AIDS. AIDS Res Hum Retroviruses 16:309–313.[CrossRef][Medline]
[Order article via Infotrieve]
- Lehner T, Doyle C, Wang Y, Babaahmady K, Whittall T, Tao L, et al. (2001). Immunogenicity of the extracellular domains of C-C chemokine receptors and the in vitro effects on simian immunodeficiency virus or HIV infectivity. J Immunol 166:7446–7455.[Abstract/Free Full Text]
- Liao F, Alkhatib G, Peden KW, Sharma G, Berger EA, Faber JM (1997). STRL33, a novel chemokine receptor-like protein, functions as a fusion cofactor for both macrophage-tropic and T cell line-tropic HIV-1. J Exp Med 185:2015–2023.[Abstract/Free Full Text]
- Lopalco L, Pastori C, Cosma A, Burastero SE, Capiluppi B, Boeri E, et al. (2000). Anti-cell antibodies in exposed seronegative individuals with HIV type 1-neutralizing activity. AIDS Res Hum Retroviruses 16:109–115.[CrossRef][Medline]
[Order article via Infotrieve]
- MacDonald KS, Embree J, Njenga S, Nagelkerke NJ, Ngatia I, Mohammed Z, et al. (1998). Mother-child class I HLA concordance increases perinatal human immunodeficiency virus type 1 transmission. J Infect Dis 177:551–556.[Medline]
[Order article via Infotrieve]
- Mackewicz C, Levy JA (1992). CD8+ cell anti-HIV activity: nonlytic suppression virus replication. AIDS Res Hum Retroviruses 8:1039–1050.[Medline]
[Order article via Infotrieve]
- Martin-Villa JM, Longas J, Arnaiz-Villena A (1999). Cyclic expression of HLA class I and II molecules on the surface of purified human spermatozoa and their control by serum inhibin B levels. Biol Reprod 61:1381–1386.[Abstract/Free Full Text]
- Medzhitov R, Janeway CA Jr (1997). Innate immunity: impact on the adaptive immune response. Curr Opin Immunol 9:4–9.[Medline]
[Order article via Infotrieve]
- Mestecky J, Kutteh WH, Jackson S (1994). Mucosal immunity in the female genital tract: relevance to vaccination efforts against the human immunodeficiency virus. AIDS Res Hum Retroviruses 10(Suppl 2):S11–S20.
- Miller CJ, McChesney M, Moore PF (1992). Langerhans cells, macrophages and lymphocyte subsets in the cervix and vagina of rhesus macaques. Lab Invest 67:628–634.[Medline]
[Order article via Infotrieve]
- Mitchell EA, Bergmeier LA, Doyle C, Brookes R, Hussain LA, Wang Y, et al. (1998). Homing of mononuclear cells from iliac lymph nodes to the genital and rectal mucosa in non-human primates. Eur J Immunol 28:3066–3074.[CrossRef][Medline]
[Order article via Infotrieve]
- Murphey-Corb M, Martin LN, Davison-Fairburn B, Montelaro RC, Miller M, West M, et al. (1989). A formalin inactivated whole SIV vaccine confers protection in macaques. Science 246:1293–1297.[Abstract/Free Full Text]
- Patterson BK, Landay A, Andersson J, Brown C, Behbahani H, Jiyamapa D, et al. (1998). Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission. Am J Pathol 153:481–490.[Abstract/Free Full Text]
- Paxton WA, Dragic T, Koup RA, Moore JP (1996). The beta-chemokines, HIV type 1 second receptors, and exposed uninfected persons. AIDS Res Hum Retroviruses 12:1203–1207.[Medline]
[Order article via Infotrieve]
- Peters B, Whittall T, Babaahmady K, Gray K, Vaughan R, Lehner T (2004). Effect of heterosexual intercourse on mucosal allo-immunisation and resistance to HIV-1 infection. Lancet 363:518–524.[CrossRef][Medline]
[Order article via Infotrieve]
- Perraut R, Lussow AR, Gavoille S, Garraud O, Matile H, Tougne C, et al. (1993). Successful primate immunization with peptides conjugated to purified protein derivative or mycobacterial heat shock proteins in the absence of adjuvants. Clin Exp Immunol 93:382–386.[Medline]
[Order article via Infotrieve]
- Piguet V, Blauvelt A (2002). Essential roles for dendritic cells in the pathogenesis and potential treatment of HIV disease. J Invest Dermatol 119:365–369.[CrossRef][Medline]
[Order article via Infotrieve]
- Piguet V, Sattentau Q (2004). Dangerous liaisons at the virological synapse. J Clin Invest 114:605–610.[CrossRef][Medline]
[Order article via Infotrieve]
- Polyanskaya N, Bergmeier LA, Sharpe SA, Cook N, Leech S, Hall G, et al. (2001). Mucosal exposure to subinfectious doses of SIV primes gut-associated antibody-secreting cells and T cells: lack of enhancement by nonneutralizing antibody. Virology 279:527–538.
- Polyanskaya N, Sharpe SA, Cook N, Leech S, Cranage MP (2003). Infection of macaques with simian immunodeficiency virus induces a species-specific antibody response to major histocompatibility complex class I and class II molecules. J Gen Virol 84:1671–1676.[Abstract/Free Full Text]
- Quayle AJ, Xu C, Mayer KH, Anderson DJ (1997). T lymphocytes and macrophages, but not motile spermatozoa, are a significant source of human immunodeficiency virus in semen. J Infect Dis 176:960–968.[Medline]
[Order article via Infotrieve]
- Ramos A, Hu DJ, Nguyen L, Phan KO, Vanichseni S, Promadej N, et al. (2002). Intersubtype human immunodeficiency virus type 1 superinfection following seroconversion to primary infection in two injection drug users. J Virol 76:7444–7452.[Abstract/Free Full Text]
- Sallusto F, Palermo B, Lenig D, Meittinen M, Matikainen S, Julkunen I, et al. (1999). Distinct patterns and kinetics of chemokine production regulate dendritic cell function. Eur J Immunol 29:1617–1625.[CrossRef][Medline]
[Order article via Infotrieve]
- Sallusto F, Mackay CR, Lanzavecchia A (2000). The role of chemokine receptors in primary, effector, and memory immune responses. Annu Rev Immunol 18:593–620.[CrossRef][Medline]
[Order article via Infotrieve]
- Shearer GM, Clerici M, Dalgleish A (1993). Alloimmunization as an AIDS vaccine? Science 262:161–162.[Free Full Text]
- Spear GT, Sha BE, Saarloos MN, Benson CA, Rydman R, Massad LS, et al. (1998). Chemokines are present in the genital tract of HIV-seropositive and HIV-seronegative women: correlation with other immune mediators. J Acquir Immune Defic Syndr Hum Retrovirol 18:454–459.[Medline]
[Order article via Infotrieve]
- Spira AI, Marx PA, Patterson BK, Mahoney J, Koup RA, Wolinsky SM, et al. (1996). Cellular targets of infection and route of viral dissemination after an intravaginal inoculation of simian immunodeficiency virus into rhesus macaques. J Exp Med 183:215–225.[Abstract/Free Full Text]
- Stevceva L, Strober W (2004). Mucosal HIV vaccines: where are we now? Curr HIV Res 2:1–10.[Medline]
[Order article via Infotrieve]
- Stott EJ (1994). Protection against simian immunodeficiency virus infection of macaques by cellular or viral antigens. In: Retroviruses of human AIDS and related animal diseases. Girard M, Dodet B, editors. Lyon, France: 9e Colloque Des Cent Gards Fondation Marcel Merieux, pp. 219–224.
- Stott EJ, Chan WL, Mills KH, Page M, Taffs F, Cranage M, et al. (1990). Preliminary report: protection of cynomolgus macaques against simian immunodeficiency virus by whole fixed infected-cell vaccine. Lancet 336:1538–1541.[CrossRef][Medline]
[Order article via Infotrieve]
- Suchin EJ, Langmuir PB, Palmer E, Sayegh MH, Wells AD, Turka LA (2001). Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 166:973–981.[Abstract/Free Full Text]
- Takeda A, Tuazon CU, Ennis FA (1988). Antibody-enhanced infection by HIV-1 via Fc receptor-mediated entry. Science 242:580–583.[Abstract/Free Full Text]
- UNAIDS (2001). WHO AIDS epidemic update: December 2001. Geneva: UNAIDS.
- Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, et al. (1998). Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 280:427–431.[Abstract/Free Full Text]
- Walker CM, Moody DJ, Stites DP, Levy JA (1986). CD8+ lymphocytes can control HIV infection in vitro by suppressing virus replication. Science 234:1563–1566.[Abstract/Free Full Text]
- Wang Y, Tao L, Mitchell E, Bogers WM, Doyle C, Bravery CA, et al. (1998). Generation of CD8 suppressor factor and beta chemokines, induced by xenogeneic immunization, in the prevention of simian immunodeficiency virus infection in macaques. Proc Natl Acad Sci USA 95:5223–5228.[Abstract/Free Full Text]
- Wang Y, Tao L, Mitchell E, Bravery C, Berlingieri P, Armstrong P (1999a). Allo-immunization elicits CD8+ T cell-derived chemokines, HIV suppressor factors and resistance to HIV infection in women. Nat Med 5:1004–1009.[CrossRef][Medline]
[Order article via Infotrieve]
- Wang Y, Tao L, Mitchell E, Bergmeier L, Doyle C, Lehner T (1999b). The effect of immunization on chemokines and CCR5 and CXCR4 coreceptor functions in SIV binding and chemotaxis. Vaccine 17:1826–1836.[CrossRef][Medline]
[Order article via Infotrieve]
- Wang Y, Kelly CG, Karttunen JT, Whittall T, Lehner PJ, Duncan L, et al. (2001). CD40 is a cellular receptor mediating mycobacterial heat shock protein 70 stimulation of CC-chemokines. Immunity 15:971–983.[CrossRef][Medline]
[Order article via Infotrieve]
- Wang Y, Underwood J, Vaughan R, Harmer A, Doyle C, Lehner T (2002a). Allo-immunization elicits CCR5 antibodies, SDF-1 chemokines, and CD8-suppressor factors that inhibit transmission of R5 and X4 HIV-1 in women. Clin Exp Immunol 129:493–501.[CrossRef][Medline]
[Order article via Infotrieve]
- Wang Y, Kelly CG, Singh M, McGowan EG, Carrara AS, Bergmeier LA, et al. (2002b). Stimulation of TH1-polarizing cytokines, C-C chemokines, maturation of dendritic cells, and adjuvant function by the peptide binding fragment of heat shock protein 70. J Immunol 169:2422–2429.[Abstract/Free Full Text]
- Wolff H, Mayer K, Seage G, Politch J, Horsburgh CR, Anderson D (1992). A comparison of HIV-1 antibody classes, titres, and specificities in paired semen and blood samples from HIV-1 seropositive men. J Acquir Immune Defic Syndr 5:65–69.[Medline]
[Order article via Infotrieve]
- WHO (2002). Report on the global HIV/AIDS epidemic 2002. Barcelona: WHO, pp. 21–41.
- Yuki Y, Kiyono H (2003). New generation of mucosal adjuvants for the induction of protective immunity. Rev Med Virol 13:293–310.[CrossRef][Medline]
[Order article via Infotrieve]
- Zaitseva M, Blauvelt A, Lee S, Lapham CK, Klaus-Kovtun V, Mostowski H, et al. (1997). Expression and function of CCR5 and CXCR4 on human Langerhans cells and macrophages: implications for HIV primary infection. Nat Med 3:1369–1375.[CrossRef][Medline]
[Order article via Infotrieve]
- Zuber B, Hinkula J, Vodros D, Lundholm P, Nilsson C, Morner A, et al. (2000). Induction of immune responses and break of tolerance by DNA against the HIV-1 coreceptor CCR5 but no protection from SIVsm challenge. Virology 278:400–411.
Advances in Dental Research, Vol. 19, No. 1,
21-28 (2006)
DOI: 10.1177/154407370601900106
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati  Twitter What's this?
This article has been cited by other articles:
|
|
|
|
 
C. Sundling, K. Schon, A. Morner, M. N. E. Forsell, R. T. Wyatt, R. Thorstensson, G. B. K. Hedestam, and N. Y. Lycke
CTA1-DD adjuvant promotes strong immunity against human immunodeficiency virus type 1 envelope glycoproteins following mucosal immunization
J. Gen. Virol.,
December 1, 2008;
89(12):
2954 - 2964.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.J. Challacombe and J.R. Naglik
The Effects of HIV Infection on Oral Mucosal Immunity
Advances in Dental Research,
April 1, 2006;
19(1):
29 - 35.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
TOP
Abstract
Introduction