The innate immune system is the first line of defense against HIV-1 and is crucial for the initial antiviral activity which reduces viral replication and protects surrounding cells from infection, as well as for the development of appropriate adaptive immune responses . To date, the vast majority of HIV-1 research has focused on the adaptive immunity in order to formulate an effective vaccine. Due to the limited success of the recent vaccine candidates [2,3], research on innate-mediated antiviral immunity is on the increase.
Following mucosal sexual transmission of HIV-1, viral RNA initially remains undetectable in the peripheral blood. Studies in the SIV-macaque model have demonstrated that infection may be initiated in dendritic cells and Langerhans cells , followed by establishment in certain CD4+ T-cell populations (40–50 cells) approximately 3–4 days after exposure [5,6]. When viral RNA, that is, HIV-1, appears in the circulation (approximately 7 days later), the CD4+ T cells in the gut are substantially depleted  and a persistent infection has already been established in the lymphatic tissue . This implies that the early stage of infection is when HIV-1 is most vulnerable, and should offer the best opportunity for rapid therapeutic intervention. In addition, HIV-1 elite controllers frequently lack the standard pathognomonic features of primary infection  and can control viral replication before the onset of adaptive immune responses . This control is not because of the intrinsic resistance of CD4+ T cells to infection [11••] and suggests the potential of innate immunity as the key determinant of HIV disease progression.
Recent findings with respect to innate-mediated immune responses against HIV-1 could lead to the development of potent microbicides/antiviral agents that can successfully prevent viral acquisition, replication and dissemination as well as valuable insights into possible adjuvants that can shape innate immune responses to enhance the effect of future vaccines.
Microbicides in genital and rectal mucosa
In addition to posing a mechanical barrier to viral entry, the host genital and rectal mucosa offers a plethora of microbicides that can prevent infection and viral replication, as well as decrease inflammation (Fig. 1) [12••,13•,14•,15–17,18•]. As existing inflammation in the mucosa, due to HIV/SIV itself or a preexisting coinfection such as HSV [19,20], aids in establishment and expansion of HIV/SIV, the anti-inflammatory properties of microbicides at mucosal sites may prevent viral dissemination. Although none of the synthetic microbicides that have completed phase III clinical trials appear to offer good protection correlates [21,22], research on novel antimicrobial molecules should generate better results. A serine protease inhibitor produced by epithelial cells in the human female reproductive tract, trappin-2/elafin, has been identified to possess both anti-inflammatory and HIV-inhibitory activities [12••], and has been associated with protection against HIV-1 acquisition .
Not all secreted antimicrobials are protective, mucosal defensins 5 and 6 increase HIV infectivity in vitro and have been proposed to have partially caused the failure of some microbicide candidates in trials [13•]. Semen-derived enhancer of viral infection (SEVI), a type of amyloid aggregates found in semen, enhance viral attachment to target cells and their levels have been correlated to HIV infectivity [14•]. In addition, HIV has developed mechanisms to exploit the human complement system by incorporating regulators of complement activation into its envelope while budding from infected host cells , leading to enhanced infection and transmission from dendritic cells to T cells . The inactivated complement fragments present on the viral surface might be involved in the induction of tolerance and immune suppression [24,25]. Of note, frequently exposed uninfected commercial sex workers expressed less complement component C3 in their genital mucosa compared with HIV-infected sex workers and uninfected low-risk groups . In the light of these findings, the effects of complement opsonization on infectivity and induction of innate immune responses are important to investigate when developing therapeutics and vaccines.
In order to successfully identify or develop agents with HIV-protective properties, the great complexity of innate-immunity regulation in human mucosa must be taken into consideration. Dissecting the roles and mechanisms of action of individual innate factors combined with a greater understanding of how they interact with and are influenced by hormonal fluctuations , coinfections [17,18•], as well as the effect of semen on the mucosal milieu and HIV susceptibility will be challenging, will be valuable tools in the development of prevention modalities.
Induction of innate immune responses through Toll-like receptor pathways
Activation of pattern recognition receptors (PRRs) of the innate immune system is crucial for early antiviral defense, which includes production of interferons (IFNs) and interferon-inducible factors (Fig. 2) [28•,29,30•,31••,32••,33•]. The most studied class of PRRs, Toll-like receptors (TLRs) have been examined to evaluate whether their signaling can be exploited to generate effective vaccines and therapeutic interventions. Although all TLRs (1–10) can be found in the human mucosa, TLR3, 4, 7, 8 and 9 preferentially induce IFN production, and thereby exhibit antiviral activity. Research showing that HIV has developed mechanisms to evade triggering TLR-induced responses [34••,35•] supports their potential as targets for innate-mediated interventions.
The major concern with TLRs is their association with inflammation and other immunoregulatory factors that may favor HIV replication and dissemination. Inducing high levels of IFN to provide potent innate antiviral immunity, but bypassing the induction of inflammation and recruitment of leukocytes to sites of infection is a challenge. Insights into which TLRs are suitable targets for HIV prevention have been generated by studies on mucosal commensal bacteria and their effect on HIV susceptibility. One study showed that in macrophages, whereas bacteria with HIV-suppressive effects preferentially stimulated TLR4, the ones that enhanced HIV replication stimulated TLR2 [28•]. These results are consistent with effects seen in dendritic cells following TLR4 and TLR2 stimulation . Furthermore, HIV inhibition through targeting TLR4 utilizing prothymosin-α, a naturally occurring TLR4 ligand produced by CD8+ T cells, potently suppressed HIV after entry into macrophages via production of type-I IFN [30•].
Stimulation of TLR3, which has been shown to act independently of inflammation , in macrophages through dsRNA (poly I:C) significantly inhibited HIV infection and replication by inducing type-I IFN inducible factors such as apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G) and tetherin [37•]. However, the suitability of TLR3 ligands for HIV suppression remains dubious as they also have been shown to increase Langerhans cell maturation and HIV transmission .
Although some results indicate that signaling through TLR9 may be HIV suppressive [39•], most studies claim that stimulation of TLR7 and TLR9 induces inflammation and augments HIV replication and spread [31••,40]. Recent results showed that phosphorothioate 2′ deoxyribose oligomers, which specifically block these TLRs, significantly inhibited the infection of peripheral blood mononuclear cells (PBMCs) by HIV [31••]. In addition, the oligomers did not appear to be toxic in vitro[31••], making them viable microbicide candidates that merit further investigation.
A possible means of avoiding inflammation resulting from TLR activation is through the use of miRNAs, which may reduce the expression of TLRs or inhibit their downstream signaling. Let-7e and miR-105 have been shown to decrease the expression of TLR4  and TLR2 , respectively, whereas miR-155 has been reported to inhibit key proteins in downstream TLR signaling . However, despite the potential advances in molecular medicine this approach may not be optimal for HIV therapy as blocking TLR signaling may impair responses to other infections and/or cell functions such as antigen presentation [44••].
In myeloid dendritic cells (mDCs), corresponding to tissue dendritic cells, HIV achieved productive infection by exploiting TLR8 signaling in combination with the C-type lectin DC-SIGN, as blocking either pathway abrogated replication and prevented HIV transmission [32••]. This mechanism could potentially be exploited to prevent infection and viral dissemination.
A study in mouse dendritic cells showed that expression of A20, an inducible feedback inhibitor of retinoid-inducible gene-1 (RIG-1), and TLR signaling pathways, inhibited robust mucosal and systemic HIV-specific cellular and humoral responses [45•]. When A20 expression was silenced it enhanced dendritic cell's ability to home to gut-associated lymphoid tissues following systemic administration, as well as inhibiting the expression of gut-homing receptors on T and B cells [45•], which would be beneficial in a HIV vaccine.
Viral restriction factors
Viral restriction factors are constitutive or IFN-induced components of the innate immune response interfering with different stages of viral replication (Fig. 3) [46,47••–49••,50,51,52•,53•,54]. Three classes of restriction factors affecting lentiviruses have been identified: cytidine deaminases, such as APOBEC3G, which induce lethal hypermutations in the viral genome; tripartite motif-containing factor (TRIM) proteins, which may affect stages of the replication cycle such as uncoating and budding; and tetherin, which prevents mature HIV particles from being released from infected cells [55,56].
APOBEC3G inhibits reverse transcription and integration events during the course of HIV's life cycle. However, upon infecting a cell, the viral protein Vif targets APOBEC3G for proteasomal degradation, abrogating or severely diminishing its antiviral functions . In addition, APOBEC3G is thought to be able to exert antiviral activity only if it is incorporated into the viral particles . Nevertheless, upregulation of APOBEC3G expression in PBMCs by immunizing macaques with SIV antigens and CCR5 peptides linked to a 70-kDa heat-shock protein (HSP) offered protection from subsequent SIV challenge . There is some concern that instead of decreasing HIV infectivity in patients, APOBEC3G upregulation may raise mutagenic activity to a level that is insufficient to render the virions noninfectious and instead aid in the evolution of drug-resistant phenotypes [52•,53•,58•]. Although recent studies have shed some light on the regulatory mechanisms of ABOBEC3G [59•,60•], it is likely that development of novel probes and research reagents will be necessary in order to dissect the mechanisms that determine what precise role APOBEC3G plays in infected cells.
Although TRIM5α is responsible for the complete block of HIV replication in Old World monkeys, its human homolog has no HIV-suppressive properties. However, the molecule PF74 has been found to prematurely uncoat HIV in target cells, by mimicking the activity of simian TRIM5α [48••]. Another IFN-induced TRIM protein which inhibits viral assembly, TRIM22, has been associated with significantly lower risk of HIV acquisition and lower viral loads or higher CD4+ T-cell counts during primary infection [49••], although its exact mechanisms of action and regulation have not yet been fully elucidated.
Ever since the discovery of its viral restriction properties in 2008 [54,61], the IFN-α-induced protein tetherin has been intensively studied. Tetherin is constitutively expressed by the plasmacytoid dendritic cells (pDCs) and restricts productive HIV cell–cell transmission [62•], as well as participating in an important negative feedback loop limiting IFN responses to viral infections . The HIV-1 protein Vpu interferes with tetherin . The fact that HIV-1 has developed highly specific tools to antagonize tetherin clearly suggests that this host restriction factor could be a potent inhibitor of viral replication in vivo.
In contrast to the factors discussed above, the peptidyl-propyl isomerase cyclophilin A (CypA) protein expressed by host cells helps in HIV replication, by binding the HIV capsid protein p24 . It has recently been discovered that a CypA inhibitor, Debio-025, blocks this interaction and reduces viral replication [47••], and may therefore have therapeutic potential.
Dendritic cells and natural killer cells
pDCs produce more type-I IFN in response to HIV than any other cell type in the body and subsequently activate mDCs and natural killer (NK) cells as well as inducing adaptive immune responses [64•,65,66••,67••,68•,69•,70] (Fig. 4). IFN-α is both beneficial, as it inhibits virus replication early during infection, and harmful, as it contributes to chronic immune activation that drives progression to AIDS . Blood pDCs and mDCs are hyperresponsive in HIV-infected individuals, indicating that they play an important role in chronic immune activation [72•]. It is hypothesized that some of the detrimental effects of chronically activated dendritic cells and extended IFN production are mediated by indoleamine 2,3-dioxygenase (IDO) which leads to disruption of Th17/Treg T-cell balance [64•,65]. In-vitro studies show that when IFN-α is blocked using chloroquine, an antimalaria drug, pDC activation is inhibited and negative modulators of T-cell responses, such as IDO and programmed death ligand-1 (PDL-1) are suppressed [66••]. The use of chloroquine along with antiretroviral therapy may interfere with chronic immune activation in infected individuals.
Although the role of pDCs in later stages of HIV infection is not clearly understood, studies show that while HIV-infected subjects with progressive disease have a significant decline in pDCs over time, elite suppressors maintain high levels of these cells , indicating that they are important factors in the innate immune response. A novel association between polymorphisms in interferon-regulatory factor-7 (IRF7), a master regulator of IFN-α, and the ability of pDCs to produce IFN-α in response to HIV-1 has recently been described [74•]. Further insight into the early events in primary infection and the underlying mechanisms behind elite controller's ability to maintain pDC levels and functions will assume paramount importance to achieve elite control of HIV replication.
NK cells interact with T cells and dendritic cells to shape the magnitude and quality of adaptive immune responses . This ‘editing process’ is impaired when the dendritic cells are infected with HIV-1, and novel findings show that this occurs because of the upregulation of two antiapoptotic molecules, cellular FLICE-inhibitory protein (c-FLIP) and cellular inhibitor of apoptosis 2 (c-IAP2) [67••]. This upregulation is reportedly controlled by high-mobility group box1 (HMGB1), a key mediator of natural killer cell–dendritic cell crosstalk. Blockade of c-FLIP and c-IAP2 or HMGB1 restored NK cell's capability to destroy HIV-infected dendritic cells [67••]. These mechanisms could possibly be targeted to eliminate infected dendritic cells early in HIV infection.
NK cells play an important role in the control of HIV infection by lysing infected cells . The exact mechanisms that mediate the recognition of HIV-infected cells are not known, detection could either occur directly, through receptor-mediated interactions that have not yet been identified, or indirectly by antibody-mediated crosslinking of CD16, an Fc receptor for IgG . HIV Vpu has recently been shown to inhibit surface expression of NTB-A (NK-cell, T-cell and B-cell antigen) in infected cells, thus protecting the cells from lysis [69•]. Also, the effects that HIV infection exerts on NK-cell functions remain to be elucidated as alteration in cell phenotype but cell levels has not been reported . Identifying the receptors responsible for NK-cell recognition of HIV and the effects HIV viremia exerts on NK-cell functions remains a key research area. One study found that HIV progressors overexpressed NKp44L on their CD4+ T cells as compared with HIV controllers and healthy donors, causing autologous NK lysis, and that this lysis was abrogated after treatment with anti-NKp44L mAb [68•]. Such research on the specific functional activity of NK cells may have important implications for the design of new anti-HIV therapeutical strategies.
Manipulating dendritic cell, macrophage and NK-cell responses may be useful strategies in vaccine development. In a mouse model, coexpression of HIV antigens and EWS-FLI1-activated transcript 2 (EAT-2), an adapter protein that leads to activation of the signaling lymphocytic activation molecule (SLAM) receptors on dendritic cells and macrophages, enhanced the induction of antigen-specific cellular immune responses and facilitated bystander activation of NK, NKT, B and T cells [77•]. Seeing that the EAT-2 adapter is conserved in both mice and humans, human vaccination strategies that specifically facilitate SLAM signaling may improve vaccine potency. The use of a genetically engineered, secreted form of heat shock protein gp96 (HSP gp96), an endoplastic-reticulum-resident chaperone, as an adjuvant in a SIV-macaque model showed some success in the induction of high levels of antigen-specific CD8+ T-cell and memory responses in rectal and vaginal mucosa [78•].
Mounting evidence suggests that innate immune responses determine susceptibility as well as disease progression in HIV infection. The goal for therapeutics targeting innate factors is a high level of protection or optimally a block of infection. Given that a recent trial has shown that mucosally applied inhibitors can confer protection from HIV-1 infection [79••], the application of potent drugs targeting innate factors present in the genital mucosa is a viable prospect for inhibiting HIV infection.
This work has been supported by the grant AI52731 from the Swedish Research Council, The Swedish Physicians against AIDS Research Foundation, The Swedish International Development Cooperation Agency, SIDA SARC, VINNMER for Vinnova, Linköping University Hospital Research Fund, CALF and The Swedish Society of Medicine.
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
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 448).
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This study shows that IDO mediates the reduction of Th17 T cells leading to the disruption of the mucosal barrier.
65. Manches O, Munn D, Fallahi A, et al
. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest 2008; 2008:10:3431–3439.
66••. Martinson J, Montoya C, Usuga X, et al. Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother 2010; 54:871–881.
This study shows that chloroquine may be useful as a therapeutic agent in HIV-infected patients with chronic immune activation as it downregulates IFN and negative T-cell responses.
67••. Melki M, Saïdi H, Dufour A, et al. Escape of HIV-1-infected dendritic cells from TRAIL-mediated NK cell cytotoxicity during NK-DC cross-talk: a pivotal role of HMGB1. PLoS Pathog 2010; 6:e1000862.
This study describes an immune evasion strategy that may be targeted for HIV inhibition once its mechanisms have been fully elucidated. The HMBG1 inhibitor used, Glycyrrhizin is in clinical use for other purposes and is anti-inflammatory, making it a viable therapeutic candidate.
68•. Vieillard V, Fausther-Bovendo H, Samri A, et al. Specific phenotypic and functional features of natural killer cells from HIV-infected long-term nonprogressors and HIV controllers. J Acquir Defic Syndr 2010; 53:564–573.
This study investigates what differences in NK-cell phenotype that aid in the control of HIV infection.
69•. Shah AH, Sowrirajan B, Davis ZB, et al. Degranulation of natural killer cells following interaction with HIV-1-infected cells is hindered by downmodulation of NTB-A by Vpu. Cell Host Microbe 2010; 8:397–409.
This study deals with a HIV strategy to avoid NK-mediated lysis of infected cells.
70. Altfeld M, Fadda L, Frleta D, Bhardwaj N. DCs and NK cells: critical effectors in the immune response to HIV-1. Nat Rev Immunol 2011; 11:176–186.
71. Herbeuvala J-P, Shearerb GM. HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol 2007; 123:121–128.
72•. Sabado R, O’Brien M, Subedi A, et al. Evidence of dysregulation of dendritic cells in primary HIV infection. Blood 2010; 116:3839–3852.
This study describes hyperresponsiveness in mDCs and pDCs and indicates that they play a key role in chronic immune activation.
73. Blankson J. Control of HIV-1 replication in elite suppressors. Discov Med 2010; 9:261–266.
74•. Chang J, Lindsay R, Kulkarni S, et al.
Polymorphisms in interferon regulatory factor 7 reduces interferon-α responses of plasmacytoid dendritic cells to HIV-1. AIDS 2011; 25:715–717.
This study elucidates the control of pDC IFN production by IRF-7. Further elucidation of the regulation of IFN production will be valuable for the control of chronic immune activation.
75. Stratov I, Chung A, Kent SJ. Robust NK cell-mediated human immunodeficiency virus (HIV)-specific antibody-dependent responses in HIV-infected subjects. J Virol 2008; 82:5450–5459.
76. Alter G, Teigen N, Davis B, et al. Sequential deregulation of NK cell subset distribution and function starting in acute HIV-1 infection. Blood 2005; 106:3366–3369.
77•. Aldhamen Y, Appledorn D, Seregin S, et al. Expression of the SLAM family of receptors adapter EAT-2 as a novel strategy for enhancing beneficial immune responses to vaccine antigens. J Immunol 2011; 186:722–732.
This study describes an adjuvant that acts by activating dendritic cells and macrophages, which may be useful in a HIV vaccine.
78•. Strbo N, Vaccari M, Pahwa S, et al. Gp96(SIV)Ig immunization induces potent polyepitope specific, multifunctional memory responses in rectal and vaginal mucosa. Vaccine 2011; 29:2619–2625.
This study suggests the use of a heat shock protein as an adjuvant to enhance mucosal vaccine responses.
79••. Abdool Karim Q, Abdool Karim S, Frohlich J, et al. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010; 329:1168–1174.
This study indicates that mucosal administration of antiviral agents can confer protection against HIV.