Introduction: Back to basics: mucosal immunity and novel HIV vaccine concepts

The 5th Axel Key symposium on ‘Mucosal Immunity and Novel HIV-vaccine Concepts’ was held in Stockholm, Sweden. This review summarizes some of the key messages and suggests areas of future scientific research priorities on HIV transmission and pathogenesis. The consensus of this meeting was that additional basic science research on HIV cell entry and mucosal immunology is likely to contribute significantly to insights that can be capitalized upon for the development of an efficacious HIV vaccine. In the current volume of the Journal of Internal Medicine, several of the symposium participants have provided comprehensive reviews of their specific fields of research on mucosal immunology. Most HIV-1 transmissions result from virus exposure at mucosal surfaces and the time-interval between initial viral exposures and detection of viral RNA in the blood is approximately 7–21 days. The cellular and molecular events that occur during the first critical hours or days after viral exposure and the establishment of a productive infection remain to be elucidated. Whilst mucosal tissue inflammation and a high viral inoculum may result in transmission of heterogeneous virus populations, a largely intact mucosal barrier and other unknown host and viral factors may only allow for more restricted viral sequences to passage the epithelial layer. Dr Hunter (Emory University) presented data on the identification of the transmitted virus and sequences evolving from it by single genome analysis that show that virus populations in the acute phase of infection were generally genetically highly homogenous. Thus, although multiple variants may be transmitted, more often single or small populations of virus are transmitted and/or there is selection of a more homogeneous viral population in the postinfection period [1] (Fig. 1). HIV-1 invasion in the genital mucosa. Viral invasion occurs through the nonkeratinized squamous epithelium of the vagina and ectocervix, as well as through the single-layer columnar epithelium of the endocervix. The endocervical mucus plug normally provides a barrier by trapping virions. Innate immune factors and the alkalinization by semen can decrease the barrier function. Virus can migrate between the stratified epithelial cells or enter through breaches. Invading HIV-1 particles may be captured and internalized into endocytic compartments by Langerhans cells (LCs) that reside within the epithelium. Interaction with the Langerin may result in degradation in the Birbeck granules, whilst binding to CCR5/CD4 may cause viral replication. Virus interaction with the epithelium induces massive MIP3-α release and subsequent accumulation of myeloid dendritic cells (mDCs). Such stromal DCs that express both DC-SIGN and CCR5 have been implicated in HIV-1 infection. The former receptor is involved in trans-infectivity whilst CCR5/CD4 interaction may lead to direct viral replication in the DCs. Most likely entrapment, antimicrobial peptide activity and C-type lectin receptor-mediated degradation dramatically reduce the pool of invasive HIV-1 quasispecies into very restricted numbers that actually reach the lamina propria. Here establishment of infection is a consequence of HIV-1 targeting CD4+ T cells that generates massive viral replication. The majority of these cells are CD45R0+ memory T cells that express higher CCR5 than those circulating in the blood. The fight back is a complex battle. HIV-1 binding to TLR7 and TLR9 result in IFN-α release in plasmacytoid DCs (pDCs) and activation of intracellular ABOPEC and other endogenous antiviral proteins. mDC derived chemokine production form a two edge sword by blocking HIV-1-CCR5 receptor utilization but also increase infectability by generating accumulation of new potential target cells. Viral induced MHC-class I down-regulation plus IFN-α and Th1 cytokines cause NK-cell activation and subsequent T cell killing of infected cells. They also produce antiviral factors that suppress replication. Formation of HIV-1-neutralizing antibodies are limited by the massive viral mutagenicity and carbohydrate-mediated shields of the critical HIV-1-envelope epitopes. These events cause inflammation including IDO-release that blocks proliferation of T cells, which can limit virus infection, but can also impair antiviral T-cell responses. A consequence of the NFκB activation is enhanced viral replication. Regulatory T cells (Treg) are accumulated that restrict the immune activation and the HIV-1 specific antiviral responses including the Th17-mediated control of mucosal microbial permeability. Establishment of the infection occurs if the infected cells are allowed to migrate to lymph nodes and lymphatic tissue of the gut. Dr Haase (University of Minnesota) described the sequential events that occur in the SIV model during the first few weeks following inoculation of virus in the female genital tract mucosa. An intact mucosal barrier indeed limits the infection of cervico-vaginal tissues and only allows a small initial founder population of infected cells. These populations must expand in order to overcome local innate immune defences that otherwise would prevent dissemination to distal sites and systemic infection. However, Dr Haase stressed that the window of vulnerability for the virus, in which there is an opportunity for preventive interventions, before its spread to the lymphatic tissues, is a matter of only a few days. Thus, the virus specific CD8+ T cell immune response may arrive on the scene too late to contain and/or eliminate the small founder populations, and perhaps only after HIV-1 has already established a latent reservoir. It suggests an extant mucosal immune response, or very rapid recall response might be able to prevent systemic infection. Dr Haase also presented data that suggested the concept that inhibiting the NFκB regulated innate and inflammatory response, which fuels the local expansion necessary to establish systemic infection, could prevent acute SIV infection. Dr Hope (Northwestern University) described ex vivo analyses of the early interactions of HIV-1 with human foreskin and cervical tissue, and of SIV in the rhesus macaque female genital tract. By labelling virions with fluorescent proteins [2] he identified SIV that had productively entered the target cells within the first few hours of virus exposure. Importantly, the virions were shown to diffuse interstitially in the intact multi-stratified epithelium of the genital tract. This was a pH-dependent process since the particles were immobilized at physiological conditions (pH = 4). In contrast, an increase in pH caused by seminal fluid permitted migration of the virions. Intraepithelial target cells such as Langerhans cells could easily establish contact with the infectious particles within the seemingly intact epithelium (Fig. 1). Breaches in the epithelium, due to sexually transmitted diseases (STDs) or physical abrasions, are thus not prerequisite for infection although such disruptions allow a more direct access of the virions to the submucosa and an extended spectrum of target cells. Furthermore, Dr Hope provided evidence that relaxation of the tight junction in inflamed tissue may facilitate the transepithelial migration of HIV-1. The generally low HIV-1 transmission rate during heterosexual vaginal intercourse is estimated to 1/200–1/2000 per exposure. Thus, the genital tissues form a protective barrier that HIV-1 has to circumvent, in addition to inhibiting factors in cervico-vaginal secretions, hindrance by the mucus layer covering the ectocervix and the endocervical mucus plug. The next barrier in the lower female genital tract is the multi-stratified epithelium of the vagina and ectocervix. Langerhans cells are amongst the first cells to encounter HIV-1 at this site. Dr Geijtenbeek (VU University Medical Center, Amsterdam) and Dr McElrath (University of Washington) have used different models for studying the role of Langerhans cells in HIV-1 transmission and they provided their insights into how this cell type may impact on the initial events in genital infections. Clearly, the function of these cells in HIV-1 transmission is complicated. HIV-1 can bind to Langerhans cells through different receptor structures including the CD4/CCR5 pathway that may result in viral replication or via initial attachment to the C-type lectin Langerin (Fig. 1). Additionally, Dr Geijtenbeek presented data showing that Langerin associated with either endosomal uptake and inactivation or spread of virions. Thus in a viral dose-dependent fashion Langerhans cells may either contain HIV-1 or efficiently transfer the virus to T cells and thereby promote subsequent systemic dissemination. Preventive strategies against HIV-1 primary infection must therefore be carefully designed in order to maintain the potential beneficial role of Langerin-HIV-1 interactions. Dr Cunningham (Westmead Millenium Institute) described the interplay between different subsets of dendritic cells (Langerhans cells as well as plasmacytoid and myeloid dendritic cells) with herpes simplex and varicella-zoster viruses. Although HIV-1 and herpes viruses interact with dendritic cells during initial infection of the genital tract, the degree of productive infection and the effects on cell maturation, IFN-release, apoptosis and subsequent cross-presentation were quite different. This reflects differences in biology and pathogenesis and has implications for understanding co-infections and the increased risk of HIV-acquisition upon concomitant herpes simplex virus infection. Indeed, CCR5 expression, which is an important infection rate limiting event for HIV-1, seems to be under the influence of local Th1 versus Th2 type of cytokine responses. The role of concomitant STDs in relation to HIV-1-acquisition in the female genital tract was further elucidated by Dr Hirbod (Karolinska Institutet). Genital tract biopsies from healthy individuals as well as from women at high-risk of acquiring HIV-1 infection were studied for identification and distribution of HIV-1 target cells. Langerhans cells were localized intra-epithelially whereas dendritic cells that express DC-SIGN and mannose-receptor (MR) were restricted to the layer of the ectocervix in both Although the numbers of dendritic cells were between the the high-risk women had significantly higher of the HIV-1 binding and DC-SIGN (Fig. 1). in and of potential HIV-1 be In Dr Geijtenbeek described the of Langerhans cells to during inflammatory It was that genital co-infections Langerhans cells by and inflammatory thereby risk of The innate against HIV-1 must be very since only a small of exposures to HIV-1 in established infection. Indeed, the mucosal fluid and the mucus layer that the cervical and vaginal in the female genital tract contain a of including cytokines and other antimicrobial These innate immune factors from cervical and as well as The genital and also that as of the innate host antiviral and By cervico-vaginal fluid from healthy Dr (University of that these innate in complex thereby potential activity at physiological An in pH and may influence the of of these factors which in the to HIV-1 an human was by Dr to be induced by and to have potential for development as a to prevent HIV-1 Dr Hirbod and Dr presented data from of women at high-risk of acquiring The of antimicrobial and proteins in the genital tract of these individuals with to the of from some of the high-risk women in HIV-1-neutralizing activity by antimicrobial (Fig. 1). This to the which also of HIV-1-neutralizing antibodies the of STDs is high in these it be to of these innate immune The of innate immune in different risk on and must be into immune responses at mucosal sites are likely to be by the in innate immune factors in target cell of mucosal innate immune may have both beneficial and effects in the in vivo some of the innate immune factors viral entry and subsequent infection, Dr Haase presented data that they also immune cells, which are potential target cells for HIV infection. A understanding of the critical of these the at the is for future human those as well as for development of The epithelial in the female and tract are thus by innate immune factors in the mucus covering the epithelium. of these factors are also within and the multi-stratified epithelial layer thereby a of before HIV-1 may reach other target cells including dendritic cells, and Dr Geijtenbeek the role of inflammatory conditions with cytokine and chemokine in the of target cells. interactions with intact epithelium as well as as a result of intercourse can inflammatory cytokine such as These can in HIV-1 replication in Langerhans cells and increase transmission to In addition to the innate immune innate cellular immune responses have a direct antiviral However, very is the local of and at the mucosal and its role in primary HIV-1 infection (Fig. 1). Dr Medical has studied during established infection and that has an impact on viral through immune Dr the of the potential of NK-cell activity in vivo on viral The of is further by which have that the of specific NK-cell cell in with their I is protective in HIV-1 these in mucosal tissue be to the of these cells for Furthermore, the of cellular at the mucosal has been suggested in of the female genital tract the HIV-1 has been shown to have different of which is immune cell are a of that are on cells and a of CD8+ T cells with an or memory or upon binding to their I thereby cell and cytokine The show Dr Institute) presented data on the identification of and their on cells in different individuals The of these variants could or to HIV-1 infection. on the for and in cell selection and of function are important to further the host impact on to HIV-1 infection and is a to how HIV-1 might with the innate immune to immune responses. cells innate and by with at the this interaction they produce cytokines and or activation of T and through innate immune also by different such is the chemokine and the antimicrobial peptide human that are and both as for the chemokine receptor are by epithelial cells and can dendritic cells and to sites of infection (Fig. 1). The role of HIV-1 in dendritic cell function and cytokine and chemokine are of future dendritic cells (pDCs) a cell type which a of a of the innate immune response (Fig. 1). The also by the to into cells. express a specific of the TLR7 and Dr the key to IFN-α production in human It is that whereas IFN-α can have a key role in the it can also have effects to if targeting TLR7 and TLR9 on human are thus likely to not on HIV infection Dr Medical presented from the HIV A pathway including two and its has been that both and innate evidence and data human that this pathway may contribute to human inflammatory It is perhaps for a single to both promote an immune response on and an immune response on T The of these to be in the genital mucosal tissue in addition to on blood cells. or activation of this pathway could a mucosal inflammatory response in the early of infection. Dr (University of that the CD8+ T cell responses in the were and including of and with low to in the of had and CD8+ T cell responses in the as to blood This suggests an important role for these responses in control of HIV-1. T-cell responses in blood were thus by important mucosal individuals with T-cell responses in blood may in and complex responses in of T-cell in the genital tract might a for understanding how at mucosal induces at other mucosal The T cells in the genital tract are from mucosal T-cell populations that express the which is a identified receptor with binding to HIV-1 and to through Dr (University of Minnesota) presented on how the to memory T-cell in cells that are not in tissues T cells were in the small epithelium and not that mucosal of may not be for the establishment of mucosal memory T-cell responses but that to more the of these responses at different mucosal Dr (University of that from vaginal is by CD8+ T cells in the vaginal of rhesus with an after vaginal SIV not the genital tract of and the only expansion of T cells in these in the CD4+ and CD8+ T cells are indeed in the lamina and epithelium of the vagina and of rhesus Thus, an mucosal memory T-cell response at the of entry may be able to limit viral replication in the genital tract and prevent the establishment of a systemic infection (Fig. 1). is the immunology in the female genital tract, in models in The role of cells and antibodies in transmission and pathogenesis as well as the innate cellular immune responses including and subsets of T cells have been a of in relation to HIV-1 infection at mucosal In addition to new insights into mucosal Dr University) data on the responses in which in both and and through both T-cell and T-cell This to production of mucosal and antibodies with potential antiviral activity Dr that the with the production of antibodies in the of the HIV-1 production which may be of a and of the very the of events during HIV-1 infection. An local immune response at both the and genital mucosal is Genital HIV-1-neutralizing has indeed been suggested to be associated with HIV in a of high-risk female However, antibodies can virus infection by and it is important to the between and antibodies with The may not for HIV-1 for may down-regulation or blocking of or responses against by HIV-1 is by and activation of T cells, due to that are largely factors caused by HIV-1 replication and of circulating factors of microbial of T-cell activation are not in of remain high viral replication in Dr on key events upon contact between HIV-1 and and suggested a model (Fig. 1). Thus, activation of and subsequent production of IFN-α and to T-cell activation and of T-cell during HIV-1 infection The may thus at a very early following primary infection. The early viral with innate immune cells, as well as with memory T-cell may in also immune responses. immune activation and to are after SIV infection in but not in this Dr (University of acute in to infection in but not systemic immune of cells and of the between and cells in and mucosal tissue was in cells were to be of systemic and T cell data thus that of the to was to has a for the release of antimicrobial and thus mucosal Thus, a new on that both and cells may a and role in the of acute HIV-1 infection. to HIV-1 Dr that can not on the of a antiviral systemic immune it may be beneficial to responses that limit mucosal of cells after acute infection the that in Such a might result in a that of the is It may lead to a response that the of immune thereby the of viral replication and Dr (University of has studied how remain high virus replication that the of CD4+ T cells, than immune control of SIV is the of viral during SIV infection of Furthermore, a of this model of infection is the of immune activation which is of the of in HIV-1 infected A understanding of the between CD4+ T cell activation and to replication as well as the of at the pool of cells are Dr of described that a of to the and an intracellular that increase on CD4+ T cells This interaction in the of the and the transmission of the virus from cell to It to be elucidated this interaction and subsequent a direct role in the of CD4+ T cells or of other immune cells. HIV-1 thus of the current in immunology. Dr of that there is an to the cell interactions and how they immune The key that Dr were to binding is in by C-type lectin binding to HIV-1 also the could also blocking with antibodies or of HIV-1 or not with the immune by immune individuals are by to HIV but remain HIV also but and HIV RNA by in blood. to with different exposure including for to to HIV infected individuals and on risk degree of exposure and of host immune several and have been associated with against the HIV-1 some of these individuals both systemic and mucosal immune responses against HIV-1 infection. the factors the of described to those to the receptor and more are likely to of the described is the between to and of the in the of the the HIV for cell presented by Dr (University of at the of the for chemokine and is the CCR5 and a HIV chemokine In Dr had a low of the was associated with an increased risk of acquiring HIV in new studied in with that the complex between the numbers of and may influence HIV Dr (University of presented a comprehensive analysis of a of female in including both and of against infection. a they cervico-vaginal fluid and this analysis proteins that were between HIV-1 women and control described such as were for in this population this is an but several with were also in the human was associated with to HIV-1 infection in these individuals Dr (University of also presented data that a factors that influence the early events of interactions have been studied by by several and against on the including Dr Medical that some express and but not individuals these can restrict viral replication. A analysis of a of of are but are able to control the virus is in order to more factors associated with of viral replication. from Dr of was also presented the of the including identified in in was Dr described data showing the between CCR5 and of in HIV-1 are and differences in the of a the of a lower than the population was shown to be associated with enhanced in multiple and This is in individuals also CCR5 This between and to a role for in pathogenesis. These factors influence HIV-1 pathogenesis by both viral and including data showing how the between the numbers of and can influence viral was also Furthermore, data was presented showing that the of a low and CCR5 was associated with cell responses during suggested that host can influence and responses during such they be further for their in of HIV-1. The was also that host may have as a in the models used for of Dr of described how a human virus systemic antibodies that to the genital tract. The concept is on particles of the This against a sexually transmitted viral infection has implications for HIV-1 research since it generates an mucosal immune in the genital tract Although HIV-1 and have very to established infection it has been shown in models that antibodies can against mucosal new for against HIV-1 were presented that could have potential for at the mucosal Dr presented an concept on HIV-1 HIV-1 and presented data on the effects of this were on of in derived dendritic cells with HIV as presented by Dr (University of and further described in Dr of that could a mucosal cellular and immune In Dr of the of human HIV-1 in models and that these be also in the future for scientific It is likely that the complex of T may more than current release for the of cellular immune responses at mucosal Dr that T are in in of such as and in to the of this response in the genital for potential protective HIV induced immune responses the innate may a HIV-1 or at a local of HIV-1 replication. This may allow for subsequent and cellular mucosal responses to occur which may HIV-1 spread and the infection under Indeed, HIV mucosal immune responses is a that to be The of the symposium was to on the research on mucosal immunology. of the from the are 1). The research has the that in and by the innate and immune This must be into and and at such as the female genital tract, different including of mucus type of of HIV-1 and of primary target cells. of innate immune defences are also at site. and inflammatory conditions further increase the of In already infected must the viral replication in local of the genital and A understanding of viral entry and dissemination at these two sites and how the immune response can limit viral production is is also a to more the the and of T and cells to the mucosal data that the mucosal to the of cells and that this from responses studied in blood. cells the mucosal tissue can also be by microbial contact and and direct both the innate and in a In must from and in of individuals at risk of HIV-1 infection as well as in infected responses are generally in blood and this may by a very restricted of cellular responses by in and responses by responses in virus is thus an to a of for of mucosal immune responses and thereby of protective The of HIV-1, the of the virus to immune the to the early establishment of latent viral and the of immune of for may have to first for a HIV-1 that viral and after infection. a of HIV-1 replication by a protective might have impact at a population The have that of and for to the

Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.