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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0b013e3283499df7
Innate immunity: Edited by William A. Paxton and Teunis B.H. Geijtenbeek

Induction of innate immunity in control of mucosal transmission of HIV

Wang, Yufei; Lehner, Thomas

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Mucosal Immunology Unit at Guy's Hospital, King's College London, London, UK

Correspondence to Dr Thomas Lehner, Tower Wing Floor 28, Guy's Hospital, London SE1 9RT, UKTel: +44 207 188 3072; fax: +44 207 288 4375; e-mail: thomas.lehner@kcl.ac.uk

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Abstract

Purpose of review: To present evidence of the role of innate mucosal immunity and to harness this arm of immunity in protection against HIV infection.

Recent findings: Dendritic cells, monocytes, natural killer (NK) cells and γδ T cells are critical in innate immunity, which is mediated by Toll-like receptor (TLR) and recently identified stress pathways. Complement factors, cytokines and chemokines have diverse functions usually affecting HIV infection indirectly. A novel group of innate intracellular HIV restriction factors has been identified – APOBEC3G, TRIM5α and tetherin – all of which are upregulated by type I interferons and some by vaccination and TLR agonists. Whereas innate immunity conventionally lacks memory, recent evidence suggests that some of the cells and intracellular factors may express immunological memory-like features.

Summary: Innate mucosal immunity may provide early effective control of HIV transmission and replication. Some vaccines can enhance innate immune factors, such as APOBEC3G and control HIV during the eclipse period, allowing full weight of neutralizing and/or cytotoxic T cells to develop and prevent mucosal HIV infection. The next generation of vaccines should be designed to target both innate and adaptive immune memory responses.

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Introduction

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 [1].

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.

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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 [4]. 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 [5]. 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 [6]. 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 [8]. 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•].

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Innate immunity and HIV infection

Studies of HIV-infected couples suggest that multiple exposures may be required for successful transmission [10], 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 [11] (Fig. 1).

Figure 1
Figure 1
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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) [12]. 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 [14]. 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 [11].

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Innate immunity can be divided into cellular, extracellular and intracellular component (Fig. 1).

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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 [11]. 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 [16].

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 [17]. NK cells are found in a variety of mucosal tissues, and in the circulation they are elevated in HIV-exposed, seronegative (ESN) individuals [18]. 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 [19]. 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 [20], and were associated with slower progression to AIDS, lower viral load and protection from infection [21].

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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) [22] or disrupting IRF3-dependent signalling pathways and innate antiviral defense during replication cycle in CD4+ T cells [23]. 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 [24]. 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 [25], possibly by upregulation of type I interferons and APOBEC3G/3F (apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G or 3F).

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CC-chemokines

The CC-chemokines RANTES, MIP-1α and MIP-1β inhibit HIV infection by blocking the HIV coreceptor CCR5 [26]. Protective role of these CC-chemokines in mucosal secretion and the circulating T cells has been shown in SIV-infected macaques [27], alloimmunization of humans [28] and HIV ESN individuals [29]. 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•].

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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 [32]. 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.

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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 [33]. 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 [35]. The low molecular mass (LMM) form of A3G [36] 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 [39]. 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 [40]. 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 [46]. 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.

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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 [51]. 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 [52]. 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) [53]. 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).

Figure 2
Figure 2
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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 [55]. 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 [56]. 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•].

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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) [57]. Moreover, increasing production of CC-chemokines was elicited in macaques following repeated immunization [58], 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 [59], viral antigens [60•], activation with the cytokines IL-12 and IL-18 [61], as well as in monocytes with allogeneic antigens [62]. 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 [62].

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.

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Conclusion

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.

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Acknowledgements

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.

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Conflicts of interest

There are no conflicts of interest.

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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

Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 447).

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References

1. Munier CM, Andersen CR, Kelleher AD. HIV vaccines: progress to date. Drugs 2011; 71:387–414.

2••. Haase AT. Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med 2011; 62:127–139.

A comprehensive review of the mechanism of HIV or SIV transmission through cervico-vaginal epithelium.

3••. Li Q, Estes JD, Schlievert PM, et al. Glycerol monolaurate prevents mucosal SIV transmission. Nature 2009; 458:1034–1038.

This study established that local inflammation which is induced by HIV gp120, plays a crucial role in initial SIV infection by recruiting SIV targeting CCR5+CD4+ T cells into the vaginal mucosa.

4. Geijtenbeek TB, Kwon DS, Torensma R, et al. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 2000; 100:587–597.

5. Zhang ZQ, Wietgrefe SW, Li Q, et al. Roles of substrate availability and infection of resting and activated CD4+ T cells in transmission and acute simian immunodeficiency virus infection. Proc Natl Acad Sci U S A 2004; 101:5640–5645.

6. Arthos J, Cicala C, Martinelli E, et al. HIV-1 envelope protein binds to and signals through integrin alpha4/beta7, the gut mucosal homing receptor for peripheral T cells. Nat Immunol 2008; 9:301–309.

7•. Saba E, Grivel JC, Vanpouille C, et al. HIV-1 sexual transmission: early events of HIV-1 infection of human cervico-vaginal tissue in an optimized ex vivo model. Mucosal Immunol 2010; 3:280–290.

This study demonstrates the cellular mechanism of HIV sexual transmission by using cervico-vaginal tissue culture model.

8. Hussain LA, Lehner T. Comparative investigation of Langerhans’ cells and potential receptors for HIV in oral, genitourinary and rectal epithelia. Immunology 1995; 85:475–484.

9•. Ganor Y, Zhou Z, Tudor D, et al. Within 1 h, HIV-1 uses viral synapses to enter efficiently the inner, but not outer, foreskin mucosa and engages Langerhans-T cell conjugates. Mucosal Immunol 2010; 3:506–522.

This study described the potential mechanisms of HIV transmission through the foreskin and the role of Langerhans cells, monocytes and CD4+ T cells in HIV infection.

10. Gray RH, Wawer MJ, Brookmeyer R, et al. Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001; 357:1149.

11. Lehner T, Wang Y, Pido-Lopez J, et al. The emerging role of innate immunity in protection against HIV-1 infection. Vaccine 2008; 26:2997–3001.

12. Mian MF, Ashkar AA. Induction of innate immune responses in the female genital tract: friend or foe of HIV-1 infection? Am J Reprod Immunol 2011; 65:344–351.

13•. DePaolo RW, Abadie V, Tang F, et al. Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens. Nature 2011; 471:220–224.

This study reported the mucosal adjuvant role of retinoic acid and IL-15 in eliciting inflammatory responses in the gut mucosal tissues and abrogation of mucosal tolerance to dietary antigens.

14. Strober W. Vitamin A rewrites the ABCs of oral tolerance. Mucosal Immunol 2008; 1:92–95.

15•. Manel N, Hogstad B, Wang Y, et al. A cryptic sensor for HIV-1 activates antiviral innate immunity in dendritic cells. Nature 2010; 476:214–219.

This study describes the potent antiviral mechanism of dendritic cells which is normally silent in HIV-1 infection, but can be activated when dendritic cells are co-infected with viral factor vpx (derived from HIV-2 or SIV) and HIV-1.

16. Kosub DA, Lehrman G, Milush JM, et al. Gamma/Delta T-cell functional responses differ after pathogenic human immunodeficiency virus and nonpathogenic simian immunodeficiency virus infections. J Virol 2008; 82:1155–1165.

17. Borrow P, Bhardwaj N. Innate immune responses in primary HIV-1 infection. Curr Opin HIV AIDS 2008; 3:36–44.

18. Montoya CJ, Velilla PA, Chougnet C, et al. Increased IFN-gamma production by NK and CD3+/CD56+ cells in sexually HIV-1-exposed but uninfected individuals. Clin Immunol 2006; 120:138–146.

19. Alter G, Teigen N, Ahern R, Streeck H, et al. Evolution of innate and adaptive effector cell functions during acute HIV-1 infection. J Inf Dis 2007; 195:1452–1460.

20. Boulet S, Song R, Kamya P, et al. HLA-devoid cells function following stimulation with genotypes influence NK cell HIV protective KIR3DL1 and HLA-B. J Immunol 2010; 184:2057–2064.

21. Martin MP, Martin MP, Gao X, et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31:429–434.

22. Yan N, Regalado-Magdos AD, Stiggelbout B, et al. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 2010; 11:1005–1013.

23. Doehle BP, Hladik F, McNevin JP, et al. Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells. J Virol 2009; 83:10395–10405.

24. Ank N, West H, Bartholdy C, et al. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol 2006; 80:4501–4509.

25. Hou W, Wang X, Ye L, et al. Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol 2009; 83:3834–3842.

26. Cocchi F, DeVico AL, Garzino-Demo A, et al. Identification of RANTES, MIP-1α, and MIP-1β as the major HIV-suppressive factors produced by CD8+ T cells. Science 1995; 270:1811–1815.

27. Lehner T, Wang Y, Cranage M, et al. Up-regulation of beta-chemokines and down-modulation of CCR5 co-receptors inhibit simian immunodeficiency virus transmission in nonhuman primates. Immunology 2000; 99:569–577.

28. Wang Y, Tao L, Mitchell E, et al. Allo-immunization elicits CD8+ T cell-derived chemokines, HIV suppressor factors and resistance to HIV infection in women. Nat Med 1999; 5:1004–1009.

29. Iqbal SM, Ball TB, Kimani J, et al. Elevated T cell counts and RANTES expression in the genital mucosa of HIV-1-resistant Kenyan commercial sex workers. J Infect Dis 2005; 192:728.

30•. Geldmacher C, Ngwenyama N, Schuetz A, et al. Preferential infection and depletion of Mycobacterium tuberculosis-specific CD4 T cells after HIV-1 infection. J Exp Med 2010; 207:2869–2881.

A study that TB antigen specific CD4+ T cells were less matured, produced low MIP-1β and high IL-2 and were susceptible to HIV infection.

31•. Hansen SG, Vieville C, Whizin N, et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. Nat Med 2009; 15:293–299.

This study demonstrated that induction of multifunctional CD4+ and CD8+ T-cell responses following vaccination is important in protection against SIV infection.

32. Moutsopoulos NM, Greenwell-Wild T, Wahl SM. Differential mucosal susceptibility in HIV-1 transmission and infection. Adv Dental Res 2006; 19:52–56.

33. Sheehy AM, Gaddis NC, Choi JD, Malim MH. Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 2002; 418:646–650.

34•. Casartelli N, Guivel-Benhassine F, Bouziat R, et al. The antiviral factor APOBEC3G improves CTL recognition of cultured HIV-infected T cells. J Exp Med 2010; 207:39–49.

Description of a novel function of A3G that is involved in eliciting effective HIV-specific CD8+ T-cell responses.

35. Santiago ML, Montano M, Benitez R, et al. Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection. Science 2008; 321:1343–1346.

36. Chiu Y-L, Soros VB, Kreisberg JF, et al. Cellular APOBEC3G restricts HIV-1 infection in resting CD4+ T cells. Nature 2005; 435:108–114.

37. Peng G, Lei KJ, Jin W, et al. Induction of APOBEC3 family proteins, a defensive maneuver underlying interferon induced anti-HIV-1 activity. J Exp Med 2006; 203:41–46.

38. Pion M, Granelli-Piperno A, Mangeat B, et al. APOBEC3G/3F mediates intrinsic resistance of monocyte-derived dendritic cells to HIV-1 infection. J Exp Med 2006; 203:2887–2893.

39. Stopak KS, Chiu YL, Kropp J, et al. Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. J Biol Chem 2007; 282:3539–3546.

40. Pido-Lopez J, Whittall T, Wang Y, et al. Stimulation of cell surface CCR5 and CD40 molecules by their ligands or by HSP70 up-regulates APOBEC3G expression in CD4(+) T cells and dendritic cells. J Immunol 2007; 178:1671–1679.

41•. Pido-Lopez J, Wang Y, Seidl T, et al. The effect of allogeneic in vitro stimulation and in vivo immunization on memory CD4(+) T-cell APOBEC3G expression and HIV-1 infectivity. Eur J Immunol 2009; 39:1956–1965.

Evidence to show both in vivo and in vitro that allostimulation induces A3G production which may protect HIV infection.

42••. Wang Y, Bergmeier LA, Stebbing R, et al. Mucosal immunization in macaques upregulates the innate APOBEC 3G antiviral factor in CD4(+) memory T cells. Vaccine 2009; 27:870–881.

This was the first study to demonstrate upregulation of long-lasting A3G in CD4+ memory subsets in vivo by mucosal immunization, which showed inverse correlation with protection against SIV infection.

43••. Sui Y, Zhu Q, Gagnon S, et al. Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques. Proc Natl Acad Sci U S A 2010; 107:9843–9848.

This study reported that the TLR agonist poly I:C and IL-15 acted as mucosal adjuvants, upregulating A3G in macaques in an antigen-independent manner and the increased A3G production was inversely correlated with viral load.

44. Stremlau M, Owens CM, Perron MJ, et al. The cytoplasmic body component TRIM5α restricts HIV-1 infection in Old World monkeys. Nature 2004; 427:848–853.

45. Sayah DM, Sokolskaja E, Berthoux L, Luban J. Cyclophilin A retrotransposition into TRIM5 explains owl monkey resistance to HIV-1. Nature 2004; 430:569–573.

46. Zhang X, Kondo M, Chen J, et al. Inhibitory effect of human TRIM5α on HIV-1 production. Microbes Infect 2010; 12:768–777.

47. Neil SJ, Zang T, Bieniasz PD. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 2008; 451:425–430.

48. Van Damme N, Goff D, Katsura C, et al. The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein. Cell Host Microbe 2008; 3:245–252.

49. Sakuma R, Mael AA, Ikeda Y. Alpha interferon enhances TRIM5alpha-mediated antiviral activities in human and rhesus monkey cells. J Virol 2007; 81:10201–10206.

50••. Schoggins JW, Wilson SJ, Panis M, et al., A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 2011. [Epub ahead of print]

Systemic analysis of ISGs involved in antiviral activity using high-throughput method by co-transfection of ISG and the virus.

51. Zhou M, Zhang A, Lin B, et al. Study of heat shock response of human umbilical vein endothelial cells (HUVECs) using cDNA microarray. Int J Hyperthermia 2007; 23:225–258.

52. Williams MS, Kwon J. T cell receptor stimulation, reactive oxygen species, and cell signalling. Free Radical Biol Med 2004; 37:1144–1151.

53. Schroder K, Zhou R, Tschopp J. The NLRP3 inflammasome: a sensor for metabolic danger? Science 2010; 327:296–300.

54•. Wang Y, Seidl T, Whittall T, et al. Stress-activated dendritic cells interact with CD4+ T cells to elicit homeostatic memory. Eur J Immunol 2010; 40:1628–1638.

Demonstration of thermal and oxidative stress stimulating dendritic cells to express IL-15 and HSP70, which can initiate CD4+ memory T cell homeostatic circuit by interaction of CD40–CD40L and IL-15–IL-15R between dendritic cells and CD4+ T cells.

55. Kaser A, Blumberg RS. Endoplasmic reticulum stress and intestinal inflammation. Mucosal Immunol 2010; 3:14–16.

56. Goodall JC, Wu C, Zhang Y, et al. Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression. PNAS 2010; 107:17698–17703.

57. Foster SL, Hargreaves DC, Medzhitov R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 2007; 447:972–978.

58. Wang Y, Tao L, Mitchell E, et al. The effect of immunization on chemokines and CCR5 and CXCR4 coreceptor functions in SIV binding and chemotaxis. Vaccine 1999; 17:1826–1836.

59. O’Leary JG, Goodarzi M, Drayton DL, von Andrian UH. T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 2006; 7:507–516.

60•. Paust S, Gill HS, Wang BZ, et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol 2010; 11:1127–1135.

Extension of the previously demonstrated hapten-specific NK memory cells to viral antigen-specific NK memory cells and the role of NK memory cells in protection against specific pathogens.

61. Cooper MA, Elliott JM, Keyel PA, et al. Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U S A 2009; 106:1915–1919.

62. Zecher D, van Rooijen N, Rothstein DM, et al. An innate response to allogeneic nonself mediated by monocytes. J Immunol 2009; 183:7810–7816.

Keywords:

APOBEC3G (A3G); HIV transmission; IL-15 and stress; mucosal tissues

© 2011 Lippincott Williams & Wilkins, Inc.

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