Mucosal innate immunity forms the first line of defense and functions during the early phase of infection, before the development of specific adaptive immune responses. The innate immune cells such as dendritic cells, monocytes, natural killer (NK) cells and γδ T cells initially have effector functions, but act later as regulatory cells in adaptive immunity. Unlike the mechanisms of adaptive immunity, the innate immune cells do not use cell-surface immunoglobulins or T-cell receptor; they are not major histocompatibility complex (MHC)-restricted and conventionally lack memory. The development of a rapid innate immune response to HIV is critical in preventing early HIV infection and destruction of more than 50% of CD4+CCR5+ T cells found mostly in mucosal tissues. Harnessing the full repertoire of innate immunity may be essential to combat HIV globe pandemic, especially in view of the largely failed clinical trials of antibody and T-cell-targeting immunogen-based HIV vaccines .
In this review, we will present some of the recent development of innate mucosal responses to HIV infection, focusing on those factors that can be upregulated through mucosal and systemic immunization. The emerging features of stress-induced activation and memory-like responses of innate immunity will be discussed.
HIV mucosal transmission
The process of HIV-1 mucosal transmission has been studied extensively in animal models and in vitro[2••]. There is evidence that the single epithelial layer of endocervix and transformation zone (between endocervix and ectocervix) has a high target cell density and turnover, which may be the site of HIV infection [3••]. Langerhans cells, a subset of dendritic cells residing in stratified squamous epithelium, may also be targeted by HIV in mucosal transmission. Langerhans cells and dendritic cells in the submucosa express the HIV receptors CD4 and coreceptors CCR5. DC-SIGN (dendritic cell-specific, intercellular adhesion molecule-grabbing nonintegrin) may also be expressed on Langerhans cells and dendritic cells. They can capture virions and mediate trans-infection of CD4+ T cells . Activated CD4+ T cells which may be recruited to the mucosal tissues by HIV/SIV (simian immunodeficiency virus)-induced inflammatory responses [3••], can interact directly with the virus to establish initial infection . The mucosal homing receptor α4β7, with high binding affinity for HIV gp120 increases CD4+CCR5+ α4β7high T-cell susceptibility to infection by HIV-1 and plays an important role in an efficient productive infection at the site of viral transmission . In most cases of heterosexual HIV transmission only few susceptible cells are infected by a single genotype of HIV [2••]. CD4+ T cells are predominantly infected with CCR5 binding (R5) viruses, despite the presence of both R5 and X4 strains of HIV in the mucosal secretions and semen. In-vitro studies suggest that CD4+ T cells derived from cervical tissues are readily infected by R5 viruses and depleted after infection, possibly by apoptosis. In contrast, X4 viruses do not replicate efficiently in cultured cervico-vaginal tissue CD4+ T cells [7•].
The foreskin may represent a major route of heterosexual transmission of HIV in males, as it contains a large number of Langerhans cells in the inner foreskin . In-vitro studies also demonstrated that Langerhans cells, as well as CD4+ T cells and macrophages in the inner foreskin can be infected within 1 h after exposure to HIV [9•].
Innate immunity and HIV infection
Studies of HIV-infected couples suggest that multiple exposures may be required for successful transmission , and this is consistent with the presence of effective mucosal innate immunity against HIV infection. The mechanism of this protection is poorly defined. Possible explanations are protective effects of the mucosal barriers, such as the mucosal structural integrity, production of mucus and low pH, limited target cell availability, and the presence of large numbers of innate immune cells and secreted factors may account for the anti-HIV activity  (Fig. 1).
A great deal of work has focused on Toll-like receptor (TLR) agonists as potential mucosal innate immune response stimulating agents. For instance CpG ODN (CpG oligodeoxynucleotides), a TLR9 agonist, TLR3 ligand poly I:C and TLR5 ligand fragellin induce production of cytokines (IFN-α, IL-1α, IL-1β, IL-6, IFN-γ) and chemokines [macrophage inflammatory protein (MIP)-1α, MIP-1β and RANTES (Regulated on Activation, Normal T Expressed and Secreted)] in the genital tract in mice and protect the animals from sexually transmitted infections (STIs) . Vitamin A metabolite retinoic acid, in a stressed intestinal environment, in the presence of IL-15, acts as a mucosal adjuvant, which activates dendritic cells to induce JNK [c-Jun N-terminal kinases, also known as MAPK8 (mitogen activated protein kinase 8)] phosphorylation and releases the proinflammatory cytokines IL-12p70 and IL-23 that promote Th1-mediated cellular and humoral responses to antigen [13•]. Dendritic cells, particularly CD103, expressing dendritic cell isolated from mesenteric lymph nodes (MLNs) and Peyer’ patches, but not from spleen, were capable of converting retinol to retinoic acid, a key mediator stimulating Tregs, effector T and B cells to express mucosal homing receptors CCR9 and α4β7 . Microbial HSP70 or 65 exert both systemic and mucosal adjuvanticity when administered with HIV antigens, inducing dendritic cell maturation, production of CC-chemokines and γδ T cells .
Innate immunity can be divided into cellular, extracellular and intracellular component (Fig. 1).
Cellular components of innate immunity
CD11c+ myeloid dendritic cells, plasmacytoid dendritic cells (pDCs), monocytes, macrophages and Langerhans cells in the mucosal tissues produce a number of soluble anti-HIV factors and stimulate antigen-specific T- and B-cell immunity. HIV can be taken up and internalized by dendritic cells, but generally they do not support HIV replication. The failure of HIV-1 replication in dendritic cells is an important mechanism utilized by HIV-1 to avoid dendritic cell-mediated anti-HIV immunity. When this is circumvented by the viral factor viral protein x (Vpx) present in SIV and HIV-2, the virus can replicate in dendritic cells. This may stimulate dendritic cells to produce potent innate anti-HIV responses, maturation of the cells and elicits rigorous adaptive immunity [15•]. It now appears that dendritic cells have a potent intrinsic anti-HIV-1 immunity, and they are not typically engaged by the virus.
γ/δ+ T cells in rectal and vaginal epithelia offer an innate defense mechanism against HIV/SIV infection through generating antiviral suppressor factors, RANTES, MIP-1α and MIP-1β . The loss of γδ T-cell function was observed in pathogenic HIV infection of humans, but not in nonpathogenic SIV-infected mangabeys, suggesting that decrease in γδ function in HIV-positive patients may contribute to HIV disease progression .
Natural killer cells combat HIV replication by noncytolytic mechanisms, direct lysis of infected cells through ‘missing-self’ mechanisms, production of antiviral cytokines (e.g. IFN-γ) and CC-chemokines or maturation of dendritic cells . NK cells are found in a variety of mucosal tissues, and in the circulation they are elevated in HIV-exposed, seronegative (ESN) individuals . The increase in NK cell function occurs before HIV-1 seroconversion, preceding the development of adaptive HIV-1-specific CD8+ T cells, and is directly correlated with the level of viral replication . NK cells expressing KIR3DL1 (killer Ig-like receptor 3DL1) alleles and their HLA-Bw4 ligands showed increased function in production of IFN-γ and TNF-α , and were associated with slower progression to AIDS, lower viral load and protection from infection .
Extracellular innate or noncognate factors
Type I interferons (α and β) are early antiviral defense mechanisms, produced predominantly by pDCs. Interferons inhibit HIV-1 replication at multiple steps in the early phase of its life cycle and thus suppress viral transmission. HIV-1 evades type I interferon pathway by either suppressing interferon production through the host factor TREX1 (a cytoplasmic exonuclease)  or disrupting IRF3-dependent signalling pathways and innate antiviral defense during replication cycle in CD4+ T cells . A new group of type III interferons (IFN-λ or IL-28/29) is structurally distinct from, but functionally similar to type I interferons and has emerged as a potent antiviral agent . Expression of IFN-λ receptors is largely restricted to epithelial cells, although IFN-λ can be induced in other cell types by TLR stimulation or viral infection. IFN-λ retains potent antiviral activity against a broad range of viruses and inhibits replication of both the laboratory and clinical strains of HIV-1 , possibly by upregulation of type I interferons and APOBEC3G/3F (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G or 3F).
The CC-chemokines RANTES, MIP-1α and MIP-1β inhibit HIV infection by blocking the HIV coreceptor CCR5 . Protective role of these CC-chemokines in mucosal secretion and the circulating T cells has been shown in SIV-infected macaques , alloimmunization of humans  and HIV ESN individuals . CD4+CD45RO+ memory T cells that express the CD57+ and CD27− differentiation markers produce high MIP-1β and low IL-2 levels, and resistance to HIV infection. In contrast CD27+ CD57− CD4+ memory T cells were associated with low levels of MIP-1β, high levels of IL-2 and susceptibility to HIV infection and rapid depletion [30•]. Highly differentiated MIP-1β-producing HIV-specific T cells induced by HIV vaccines expressed in replication-competent, recombinant CMV (Cytomegalovirus) were also associated with protection against SIV challenge [31•].
Anti-HIV proteins and peptides in mucosal secretions
A collection of cationic proteins are present in mucosal fluids which have HIV inhibitory activity, including defensins, secretory leukocyte protease inhibitor (SLPI), lactoferrin, other proteins and mucus . Although only SLPI and defensins have been studied extensively for their HIV inhibitory effects it is believed that the sum total of cationic proteins may serve as a critical defense mechanism against infection in the genital and rectal mucosa.
Intracellular innate antiviral factor
Several important intrinsic host defense systems have been identified which play a key role in restricting retroviral infection and limiting HIV-1 replication, including A3G, tripartite motif (TRIM)5α and tetherin. HIV-1 and other primate lentiviruses have evolved specific means to antagonize these host restriction factors, which allow HIV-1 to replicate in the presence of intrinsic innate restriction. For instance, HIV-1 viral infection factor (Vif) counteracts A3G and protects the virus by preventing incorporation of A3G into virions and by rapidly inducing its ubiquitination and proteasomal degradation.
A3G is an intracellular antiviral factor with a molecular mass of 46 kDa. It is packaged into retroviral virions and deaminates viral cytidine to uridine, or by a nonediting mechanism rendering them nonfunctional and inhibiting viral replication . The innate antiretroviral activity of the APOBEC family also regulates T- and B-cell-mediated adaptive immunity by enhancing HIV-specific CTLs [34•] and neutralizing antibody response against Friend virus . The low molecular mass (LMM) form of A3G  is resistant to the actions of Vif, making it more desirable as an anti-HIV agent than its non-Vif-resistant high molecular mass (HMM) A3G counterpart. Expression of A3G in macrophages and dendritic cells is upregulated by type I interferons [37,38], and in T cells by mitogens (PHA), phorbol esters and the cytokines IL-2 and IL-15 . Engaging the receptors CCR5 and CD40 molecules with the chemokine CCL3 and the CD40 ligand (CD154), respectively, or both receptors by HSP70, enhances A3G expression in dendritic cells, monocytes and CD4+ T cells through activation of the ERK 1/2 and p38 MAP kinase signalling pathways . Allostimulation also upregulates A3G expression in CD4+ T cells, especially CD4+CD45RO+CCR7− effector memory T cells [41•].
In-vivo upregulation of A3G was demonstrated in rhesus macaques by mucosal immunization with SIV antigens and CCR5 peptides, linked to microbial HSP70 [42••] or poly I:C combined with the cytokine IL-15 [43••]. An increase of A3G was found in mucosal lymph node dendritic cells, monocytes, CD4+CCR5+ T cells, as wells as in rectal and colonic mucosal T cells [42••,43••] and is independent of specific antigen stimulation [43••]. Increase in A3G mRNA in the eluted rectal cells, CD4+CCR5+ circulating cells and the draining iliac lymph node cells was associated with protection against mucosal SIV challenge. In contrast the small intestinal mucosa and the unrelated axillary lymph nodes showed no corresponding difference in A3G mRNA between the uninfected and infected animals [42••], consistent with a protective effect exerted by A3G in the recto-colonic mucosa [43••].
TRIM5α was originally identified as a host factor in simian cells to restrict HIV-1 but not SIVmac infection [44,45], but recently in a knockdown experiment the endogenous human TRIM5α inhibited HIV-1 production . Tetherin (also known as CD317. BST-2 or HM1.24) inhibits viral release by ‘tethering’ mature virions to the cell surface [47,48]. Although all restriction factors are constitutively expressed by variety of cell types, their expression can be upregulated by interferons [47,49], so that manipulating these host restriction factors could provide an important alternative approach to developing effective HIV vaccines. Indeed, more than 380 other interferon-stimulating genes (ISGs) have recently been identified and screened [50••]. Combined expression of pairs of some of these ISGs showed additive antiviral effects.
Stress-induced activation of innate immunity
Thermal or oxidative stress response induces a series of structural and functional changes in the cells, including activation of genes related to heat shock responses, cellular communication, signal transduction and cell growth arrest . Oxidative stress can be caused by a number of pathological conditions, such as bacterial, HIV and fungal infections, hyper-thermia or hypo-thermia, toxins and radiation. Low levels of oxidative stress may elicit activation of protein kinases, transcription factors and the production of cytokines . Oxidative stress also activates inflammasomes, the intracellular macromolecular complexes which are comprised of a nod-like receptor (NLR) family member, an adaptor protein, and a caspase recruitment domain (CARD) . Inflammasomes may function as intracellular sensors of danger and lead to production of IL-1β, a key mediator of inflammation and adjuvanticity.
We have demonstrated that thermal or oxidizing stress-activated dendritic cells interact with CD4+ T cells to induce and maintain a T-cell receptor-independent homeostatic memory circuit. Stress-activated dendritic cells express endogenous intracellular and cell surface HSP70. The NF-κB signalling pathway is activated, which leads to expression of membrane-associated IL-15 molecules. These interact with the IL-15 receptor complex on CD4+ T cells, activating Jak3 and STAT5 phosphorylation signalling pathway, to induce CD40L expression, antigen-independent CD45RO+CD62L+ central memory T-cell proliferation and IFN-γ production. CD40L on CD4+ T cells in turn re-activates CD40 molecules on dendritic cells, thereby maintaining a feedback circuit [54•] (Fig. 2). These findings have been extended to in-vivo studies and suggest that stress can activate a dendritic cell–CD4+ T-cell-interacting circuit, which may be responsible for maintaining a homeostatic antigen-independent memory and elicit anti-HIV immunity [54•] (Wang et al., manuscript in preparation).
Mucosal epithelial cells, plasma cells and dendritic cells, reside in an environment of a large collection of commensal microbes and are therefore susceptible to environmental pressure that causes accumulation of misfolded or unfolded proteins within the endoplasmic reticulum (ER) and promote ER stress. ER stress has been recently recognized as a mechanism for maintaining epithelial homeostasis, detecting malfunctions in cellular physiology and responding to external threat posed by infectious agents . Activation of ER stress of dendritic cells, in combination with TLR agonists, markedly enhanced dendritic cell production of IL-23 through induction of transcription factor C/EBP homologous protein (CHOP), but not IL-12, suggesting that integral ER-stress signals play a role in dendritic cell modulation of T-cell function through IL-12 and IL-23 production . In a stressed intestinal environment, retinoic acid in the presence of IL-15 activates innate immunity that promotes Th1-mediated inflammatory cellular and humoral responses [13•].
Putative memory of innate immunity
Memory is a critical function of adaptive immunity and confers specific protection in peripheral tissues by mounting recall responses to antigens in secondary lymphoid organs. However, certain genes, particularly those encoding antimicrobial molecules, may enhance their function after repeated stimulation of TLR in macrophages with LPS (lipopolysaccharide) . Moreover, increasing production of CC-chemokines was elicited in macaques following repeated immunization , suggesting that the noncognate chemokines may elicit a memory-like response. NK cells are innate immune cells and yet memory-like features were demonstrated in murine NK cells with haptens , viral antigens [60•], activation with the cytokines IL-12 and IL-18 , as well as in monocytes with allogeneic antigens . In these studies the response persisted for more than 4 weeks after initial priming, it was transferable to naïve animals by primed NK cells or monocytes and conferred protection to the specific antigen or pathogen [59,60•,61,62]. The molecular basis for the innate immune cell memory is unclear. CXCR6 seems to be required for the persistence of memory NK cells [60•], whilst monocyte-mediated allogeneic memory responses were independent of MHC loci in RAG (recombination activating gene)-deficient mice .
Mucosal immunization of macaques with HSP70 linked to CCR5 peptides and HIV antigens elicited progressive increase in A3G mRNA detected in PBMC after each immunization, which was maintained for at least 17 weeks [42••]. Longevity of A3G was also demonstrated in a separate study in immunized macaques, which was induced by the adjuvant and was independent of antigens [43••]. Immunization significantly upregulated A3G mRNA in CD4+CCR5+ memory T cells in the circulation, spleen, lymph nodes and rectal mucosal tissue. Furthermore, A3G proteins were significantly upregulated in CD4+CD95+CCR7− effector memory T cells. After SIV mac251 infection, despite a significant loss of CD4+CD95+ memory T cells, the remaining memory CD4+ T cells expressed significant levels of A3G [42••], which suggested that increased A3G expression can confer CD4+ memory T cells resistant to SIV infection and virus induced cell depletion.
Mucosal innate immunity may provide the most effective protection against mucosal transmission of HIV during the early window of opportunity, covering the critical interval before effective immune responses develop and clear or control any residual infection. A great deal of further work will be required to harness the entire repertoire of innate antiviral factors that include A3G, tetherin, TRIM5α and other HIV-restricting factors. This is a challenging and certainly promising new field of inquiry. The example of homozygous Δ32CCR5 mutation that confers near-complete resistance to HIV acquisition has demonstrated the most effective ‘natural immunity’ against HIV-1 infection. There is a need to identify new strategies that can enhance these restricting molecules, or inhibit viral factors such as vif or vpu (or nef) which oppose the function of A3G and tetherin, respectively. The emerging evidence that immunological memory may be elicited in innate immune responses, especially related to NK cells, monocytes and A3G has raised the possibility of inducing long-lasting innate responses by vaccines designed to target not only classical adaptive but also innate immunity.
The study was supported by the EU grants MUVAPRED (LSHP-CT-2003–503240), Allomicrovac (LSHP-CT-2007–036928), EU Network of Excenlence, Europrise (LSHP-CT-2006–037611) and Gates Foundation. The authors would like to thank Drs Trevor Whittall, Thomas Seidl and Kaboutar Babaahmady for their inputs and help in this project.
Conflicts of interest
There are no conflicts of interest.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
* • of special interest
* •• of outstanding interest
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