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ScienceDirect Viral and cellular mechanisms of the innate immune sensing of HIV Xavier Lahaye1,2 and Nicolas Manel1,2 HIV-1 replicates in immune cells that normally respond to incoming viruses and induce antiviral immune responses. Under this constant surveillance, how HIV-1 interacts with the host to escape immune control and causes immunopathology is still being untangled. Recently, a series of HIV-1 interactions with innate sensors of viruses expressed by immune target cells have been identified. Here, we review the HIV-1 factors that escape, engage and regulate these innate immune sensors. We discuss the general principles of these interactions as well as the remarkable cell-type specificity of the regulatory mechanisms and their resulting immune responses. Innate sensors directly intersect viral replication with immunity, and understanding their triggering, or lack thereof, improves our ability to design immune interventions. Addresses 1 Institut Curie, 12 rue Lhomond, 75005 Paris, France 2 INSERM U932, 12 rue Lhomond, 75005 Paris, France Corresponding author: Manel, Nicolas ([email protected])
Current Opinion in Virology 2015, 11:55–62 This review comes from a themed issue on Viral pathogenesis Edited by Matteo Iannacone and Luca Giudotti
http://dx.doi.org/10.1016/j.coviro.2015.01.013 1879-6257/# 2015 Elsevier Ltd. All rights reserved.
Introduction While HIV-1 induces an immune response in the infected host, this response is unable to sterilize infection and generally poor at controlling viral replication, leading to AIDS. The tropism for HIV-1 to immune cells suggests that viral replication in the immune system disables it, which leads to AIDS-induced pathogenesis [1]. However, how HIV-1 escapes protective immunity in a host that is initially immunocompetent is still unresolved. Furthermore, what are the processes of viral replication that lead to immunodeficiency remains a disputed question. In the recent year, the identification of HIV-1 interactions with the innate immune system has provided fresh views on these two important problems. At the core of the innate immune system are innate immune sensing pathways, which consist of non-clonal processes that relay changes in host state to immunity. In the context of HIV-1, these www.sciencedirect.com
changes can be directly induced by the virus, as well as indirectly through tissue damages and disruptions of cellular integrity, for example. Here, we will review the main implications of HIV-1 proteins and nucleic acids in innate immune sensing and the underlying cellular and molecular mechanisms.
Viral nucleic acids Sensing of viral nucleic acids by TLRs
The HIV viral particles contain two copies of the viral genome as ssRNA. TLRs constitute the first line of sensors encountered by HIV in the form of exogenous viral particles. Among all TLRs, TLR7 and TLR8 have the capacity to recognize the genomic ssRNA of HIV [2] (Table 1). Recognition of the HIV-1 ssRNA has been best analyzed in plasmacytoid dendritic cells (pDCs) thanks to the rapid and strong production of type I interferon that ensues [3]. In pDCs, recognition is mediated by TLR7 [4], occurs in an endosomal compartment [5,6], does not require productive viral replication [6] and leads to the production of IFNa and TNFa [5]. Recognition of the HIV-1 RNA by TLR7 and TLR8 has also been observed in monocytes and monocyte-derived dendritic cells (MDDCs). In monocytes, it has been shown that recognition of the HIV-1-derived ssRNA by TLR7 and TLR8 leads to production of IL6 and TNFa in one study [7], while infection of monocytes by HIV-1 was proposed to induce inflammasome activation but not production of IFNs in other studies [8,9]. In MDDCs, in contrast, it has been proposed that recognition of the HIV-1 RNA by TLR7 and TLR8 signals to increase subsequent viral transcription and hence viral production by the cells and no immune response was reported [10]. Finally, it was recently proposed that TLR7 expression in CD4+ T cells is functional for recognition of the HIV-1 RNA [11]. The outcome is complex as it induces simultaneously anergy of the T cells and an increase in viral production. The viral particles contain also additional nucleic acids, such as the cell-derived tRNA used for priming reverse transcription, and there putative recognition by TLRs remains an intriguing possibility. Overall, the viral genome in viral particles has clearly emerged as an important viral nucleic acid for TLR activation. After viral fusion with the cell, HIV-1 particles release their capsid in the cytosol, which contains the viral ssRNA. It is reverse transcribed in viral cDNA, which is transported to the nuclear genome for integration. During these processes, the virus-derived nucleic acids that are generated are putative triggers for innate immune Current Opinion in Virology 2015, 11:55–62
56 Viral pathogenesis
Table 1 Viral factors in HIV-1 that are directly recognized by innate sensors Viral factor ssRNA in the particle
Viral dsDNA and related RT products
Innate sensor
Refs
TLR7 in pDCs
Type I IFN
[2 ,3,5]
TLR7 and TLR8 in monocytes
IL1b, IL6 and TNFa
[7–9]
cGAS recognition in MDDCs
Type I IFN and activation of antigen presentation when SAMHD1 is abrogated Type I IFN when CypA or CPSF6 are inhibited Type I IFN when TREX1 is absent IL1b and pyroptosis; type I IFN
[20,21]
Type I IFN
[15]
Inflammatory cytokines production
[42,43]
Unknown sensor in MDMs cGAS in TREX1-deficient MDMs IFI16 in tonsilar CD4+ T cells recognition Unknown sensor in SLX4-inhibited cell lines Membrane-tethered viral particles
Innate immune response to the viral component
Tetherin
sensors. These include potentially a wide range of nucleic acid species: dsDNA, structured ssRNA, short ssDNA, linear ssRNA, hybrids RNA:DNA and degradation or modified products. In the past years, a series of studies have described that HIV-derived DNA species can activate cytosolic innate sensors [12,13,14,15,16] (Table 1). Sensing of cytosolic viral nucleic acids in dendritic cells
In MDDCs, HIV-1 infection does not normally induce an innate immune response (Figure 1a) [12,17]. Bypassing the SAMHD1 restriction [18,19] upon infection with the viral Vpx protein (see below for the role of Vpx) leads to production of type I interferon and innate immune activation (Figure 1b). Accordingly, HIV-2, which naturally encodes Vpx, also induces this response. In HIV-2, it requires the presence of the viral cDNA in the cytosol, but does not require nuclear entry of the genome and viral integration (Figure 1c). In HIV-1, activation further requires integration and expression of newly synthesized capsid [12] (see below for the role of capsid) (Figure 1b). In both cases, the DNA sensor cyclic GMP–AMP synthase (cGAS) is required, a sensor that produces the second messenger cyclic GMP–AMP (cGAMP) [20,21]. cGAMP has a high affinity for STING, an ER-resident protein, and its binding to STING induces the recruitment of a signaling machinery that ultimately leads to activation of IRF3. The requirement for cGAS indicates that the cytosolic viral cDNA is required for sensing in the case of HIV-1, even if the incoming viral capsid is not permissive. Overall, the viral cDNA is thus essential for innate sensing of the virus, but it is constrained by the viral capsid context: depending on its amino acid sequence and interaction with cofactors (see below), the viral capsid has the ability to either shield the viral cDNA away from innate sensors or favor the viral cDNA access to sensors. HIV-1 can replicate to some extent in DCs when SAMHD1 is active (in the absence of Vpx) leading to a Current Opinion in Virology 2015, 11:55–62
[22] [14,20] [16,23,64]
significant fraction of infected cells. However, this does not trigger an innate immune response and sensing requires alleviation of SAMHD1 restriction [12]. Even with Vpx, it is not necessarily all the infected cells at a given rate of infection that trigger an innate immune response [12]. Here, it should be noted that SAMHD1 impacts the efficiency of reverse transcription in the cytosol and that the frequency of infected cells (as indicated by viral or reporter protein expression) does not necessarily reflect the total amount of viral cDNA in the cytosol. At a given frequency of infected cells, it is likely that cells without SAMHD1 contain a much larger pool of cytosolic cDNA sufficient to activate cGAS, whereas in the presence of SAMHD1, the quantity of cytosolic viral cDNA produced does not reach a sufficient threshold to trigger cGAS. The relative abundance of these cytosolic pools may not necessarily relate to the infection rate of the cell. Indeed, it is very likely that several steps after reverse transcription are saturable and/ or that not all RT products are competent for transport to the nucleus and integration. When considering these innate immune sensing pathways, it is essential to consider the relevant viral material (e.g. the amount of cytosolic viral cDNA and the capsid), and not only the apparent infection rate of the cells. Sensing of cytosolic viral nucleic acids in CD4+ T cells and macrophages
In monocyte-derived macrophages (MDMs) and CD4+ lymphocytes, HIV-1 infection proceeds and does not normally induce detectable type I interferon production [14,22] (Figure 1d). However, in the absence of TREX1, a DNA exonuclease, HIV-1 infection induces a type I interferon response [14]. It is thought that TREX1 normally degrades by-products of the viral reverse transcription process, and these products accumulate in the absence of TREX1, leading to innate sensor activation. The response in TREX1-deficient cells requires the DNA sensor cGAS [20] as well as STING, TBK1 and IRF3. In addition to TREX1-deficient cells, www.sciencedirect.com
HIV sensing in innate immunity Lahaye and Manel 57
Figure 1
Monocyte-derived dendritic cells HIV-1
(a)
(b) HIV-1, with Vpx
CypA
Monocyte-derived macrophages HIV-2
(c)
HIV-1, with inhibition of (e) CypA or CPSF6
HIV-1
(d)
CypA
CypA
CPSF6
dNs
cGAS
cGAS
VPX
cGAS
VPX
dNTPs
dNs
cGAS
dNTPs SAMHD1
SAMHD1
cGAS ?
dNs dNTPs SAMHD1
Integrated proviral DNA
Current Opinion in Virology
Cytosolic sensing of HIV in monocyte-derived macrophages and monocyte-derived dendritic cells. For clarity, the impact of the innate immune responses on viral replication and on the other cells of the immune system is not depicted. (a) In MDDCs, HIV-1 infection is highly restricted by SAMHD1 and does not trigger an interferon response or dendritic cell activation. (b) When SAMHD1 is abrogated with Vpx, HIV-1 infects efficiently the MDDCs and triggers an innate immune response through cGAS. The incoming viral capsid initially shields viral DNA sensing by cGAS. Newly synthesized capsid production after viral integration and interaction with CypA (depicted as Gag bound to CypA) is required to render the viral DNA susceptible to sensing by cGAS. (c) HIV-2 abrogates SAMHD1 after viral entry leading to an efficient infection of the cells and to induction of an innate immune response. In contrast to HIV-1, the incoming capsid is permissive for sensing of the viral cDNA by cGAS before nuclear entry and integration. (d) In MDMs, HIV-1 infection does not trigger innate sensors. Although infection is presumably less restricted than in MDDCs by SAMHD1, the capsid interacts with CypA and CPSF6 and prevents innate sensor activation. (e) When CypA or CPSF6 are inhibited, the capsid is permissive and HIV-1 induces a type I interferon response triggered by the viral DNA. cGAS is a suspected sensor for this response.
induction of IFN by HIV-1 was reported in MDMs when interaction of the viral capsid with host factors was perturbed (see below for the role of capsid) [22]. In this setting, sensing also requires reverse transcription and the production of cGAMP was detected, suggesting that cGAS is also implicated and recognizes the viral cDNA. How this sensing occurs despite the presence of functional TREX1 is not understood. Finally, in CD4+ T cells from tonsil, sensing of abortive reverse transcription leads to induction of caspase-1-dependent pyroptosis. In these cells, the DNA sensor IFI16 binds to the viral DNA and is required for induction of pyroptosis [16,23].
is capped and polyA-tailed, alike host messenger RNAs, which may contribute to the lack of responses. Additionally, it remains possible that a TREX1-like activity against viral ssRNA, such as SKIV2L, may prevent such response [24]. Summarizing, in the cytosol, the products of reverse transcription constitute various substrates for the innate immune sensors cGAS and IFI16. The resulting immune responses are diverse and show a high level of cell-type specificity, but still need to be further characterized (Table 1).
In contrast to reverse transcription products, the incoming viral ssRNA has not been reported to trigger innate immune sensing pathways. The genomic RNA of HIV
Several studies have shown that the viral capsid protein is a key regulatory factor of innate sensing pathway through its binding to host factors (Table 2).
Viral capsid protein and capsid-interacting proteins
Table 2 Viral proteins that interact with host factors and regulate innate sensing Viral protein
Interacting host factor
Impact on innate sensing
Refs.
Capsid in Gag
CypA in MDDCs CypA in MDMs CPSF6 in MDMs TRIMCyp in simian cells
Promotes cGAS-dependent sensing of viral DNA Prevents innate sensing of viral DNA Prevents innate sensing of viral DNA Inflammatory cytokines
[12,21] [22] [22] [39]
Vpu Vpr Vpx
Tetherin SLX4 SAMHD1 in MDDCs
Prevents sensing of membrane-tethered viral particles Prevents innate sensing of viral DNA Promotes innate sensing of viral DNA
[42,43] [15] [12,21]
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Capsid and CypA
Cyclophilin A (CypA), a peptididyl prolylisomerase, is the first host protein shown to directly bind to the viral capsid on a loop in the N-terminal domain [25]. CypA is incorporated into viral particles [26,27]. Loss of interaction, by Cyclosporin A treatment or silencing leads to a reduction of HIV infectivity due to a block in replication in several but not all cell types, indicative that CypA can promote HIV-1 infectivity and replication, although the underlying mechanism has still not been resolved [25,26]. In MDDCs and MDMs, innate sensing of the HIV-1 cDNA is regulated by capsid and its interactions with CypA, and the HIV-1 capsid normally prevents premature innate immune sensing of the viral cDNA before integration (Figure 1a,d) but there are key differences. In MDDCs with Vpx, the HIV-1 capsid prevents innate immune sensing of the viral cDNA before integration, and sensing is triggered when newly synthesized capsid is produced after viral integration and expression [12] (Figure 1b). This sensing of HIV-1 by MDDCs requires CypA binding to capsid. In MDMs, sensing is in contrast prevented by CypA (Figure 1d) and, when CypA binding to capsid is abrogated, sensing occurs before nuclear entry and despite the presence of SAMHD1 and TREX1 [22] (Figure 1e). In MDDCs, a comparable inhibition of CypA does not lead to induction of interferon after infection with HIV-1 by itself [12]. Thus, CypA regulates innate sensing in a cell-type specific manner, with opposite outcomes in MDMs versus MDDCs. This may not be a surprise, given the well-recognized cell-type specific role of CypA in infection [28]. In MDDCs, the analysis of innate sensing was extended to HIV-2, which naturally contains Vpx (Figure 1c) [12]. Sensing of HIV-2 also requires Vpx, cGAS and the viral cDNA. In contrast to HIV-1, HIV-2 capsid binds weakly CypA and it is permissive to sensing of the viral cDNA before integration, while simultaneously allowing nuclear entry and productive viral infection (Figure 1c) [21]. In both HIV-1 and HIV-2, increasing the affinity of the capsids to CypA renders the capsid strongly favorable for innate sensing of the viral cDNA and concurrently much less capable at leading to a productive viral infection [21]. Overall, HIV-1 has evolved to minimize triggering of innate DNA sensors in dendritic cells and macrophages, through a combination of a limited reverse transcription in these cells (due to SAMHD1) and an optimal capsid protein in interaction with CypA.
capsid is required to prevent premature sensing of the viral cDNA (Figure 1d). Abrogating CPSF6 expression or its binding to capsid (N74D mutation in capsid) allows HIV-1 to induce an interferon response in MDMs [22] (Figure 1e). Thus, CPSF6 plays an analogous role to CypA in this model. It was speculated that these factors prevent premature reverse transcription in macrophages in a way that prevents innate sensing, although it remains unclear how timing of reverse transcription can influence the fate of the viral cDNA. Other capsid interacting factors
The HIV viral capsid has been reported to interact biochemically or genetically with a wealth of other factor, including TRIM5a, MX2, TNPO3, NUP153, RANBP2. Among them, MX2 is an IFN-inducible resistance gene that has antiviral activity against HIV-1 [33–35]. MX2 targets incoming virus in a CypA-dependent manner and inhibits the viral DNA nuclear import [33–35]. Interestingly, MX2 localizes to the cytoplasmic side of nuclear pores and has been suggested to regulate nucleocytoplamic transport [36]. It is thus tempting to speculate that MX2 activity may impact innate immune sensing pathways of the viral cDNA. TRIM5a has been linked to the regulation of LPS signaling and can function as a sensor for capsid lattice of retroviruses, but human TRIM5a does not bind to the HIV-1 capsid [37,38] and thus unlikely behaves as an HIV-1 sensor in human cells [39]. Overall, it will be important to examine the putative contribution of these factors to innate immune sensing pathways. To summarize, the HIV-1 capsid has emerged as a major determinant of the fate of the viral cDNA toward innate immune sensors, at least in myeloid target cells. It is likely that the intrinsic stability of the capsid has a major role in preventing exposure of the viral cDNA to sensors before its entry into the nucleus. In addition, the binding of host factors to capsid determines the fate of the cDNA. Intriguingly, CypA appears to function differently in MDMs vs. MDDCs. This may result at least from a differential role of SAMHD1 or from other capsid-interacting factors.
Accessory proteins HIV encodes accessory proteins that regulate specific aspects of the viral replication. Among them, Vpu and Vpr in HIV-1, and the closely related Vpx in HIV-2/ SIVmac have emerged as key regulators of the interaction of HIV with the innate sensors (Table 2).
Capsid and CPSF6
Cleavage and polyadenylation specific factor 6 (CPSF6) is a nuclear host protein that binds the viral capsid adjacently to the CypA binding loop [29,30]. CPSF6 is actively transported to the nucleus by TNPO3, which appears to be the main function of TNPO3 in the viral cycle [31,32]. In MDMs, it was shown that CPSF6 binding to Current Opinion in Virology 2015, 11:55–62
Vpu
Vpu antagonizes the restriction enforced by Tetherin on viral release [40,41]. In the absence of Vpu, Tetherin also functions as an innate immune sensor triggered by the cell surface retention of viral particles [42]. The physical clustering of Tetherin by trapped viral particles www.sciencedirect.com
HIV sensing in innate immunity Lahaye and Manel 59
induces NF-kB signaling that induces expression of proinflammatory cytokines CXCL10, IL6 and IFNb [42,43]. Release of cytokines by cells infected with a Vpu-defective virus confers an antiviral state to bystander cells [43]. It will be important to determine to what extent this release of cytokines may contribute to shaping the innate and adaptive immune response during the infection. Vpr
Vpr was recently implicated in the regulation of innate immunity through its binding to the SLX4 protein [15], a coordinator of endonucleases normally implicated in the resolution of DNA structures generated during DNA replication and repair, such as Holliday junctions. Vpr directly binds to both SLX4 and VPRBP, an E3-ubiquitin ligase. This combined recruitment leads to the enhancement of the endonuclease activity of MUS81 and EME1, the endonucleases normally regulated by SLX4. In HeLa cells, depleting SLX4, VPRBP or MUS81 expression leads to an increase in type I interferon expression independently of viral infection, indicating that these proteins are negative regulators of an endogenous production of type I interferon [15]. In addition, infection of HeLa cells with a virus defective for Vpr leads to a small increase in type I interferon and MxA expression, as well as an increase in the total amount of viral DNA in the cell. Furthermore, the viral DNA interacts with SLX4 in the presence of Vpr [15]. This suggests that Vpr-mediated activation of the SLX4 complex plays a role similar to TREX1 in limiting the pool of viral DNA available to cytosolic sensors. Intriguingly, the magnitude of interferon induction in HeLa cells in the absence of Vpr is small. It is plausible that TREX1 and capsid contribute to this limited interferon induction detected in the absence of Vpr in Hela cells, and it will be important to establish the status of this pathway in primary target cells of the virus. Vpx
SAMHD1 restricts HIV-1 replication in myeloid cells [18,19] and resting CD4+ T cells [44,45]. HIV-1 does not encode a protein to abrogate the SAMHD1 restriction. In contrast, the related virus HIV-2 encodes the Vpx protein, closely related to Vpr, that recruits SAMHD1 and VPRBP, leading to degradation of SAMHD1. SAMHD1 is an Aicardi-Goutie`res syndrome gene [46] that functions as a dNTP hydrolase [47] and possibly as a RNA endonuclease to limit HIV replication at the level of reverse transcription [48]. In MDDCs, Vpx is required for type I interferon induction and activation of antigen presentation by HIV-1 (by way of complementation) and by HIV2. We previously described the role of the viral DNA and capsid in this induction. Intriguingly, HIV-2 is less pathogenic than HIV-1 presumably due to a contribution of a more effective immune response [49,50]. This led to the hypothesis that induction of an innate immune response by HIV-2, and its lack thereof in HIV-1, could contribute the better outcome of HIV-2 infection. www.sciencedirect.com
Why HIV-2 would encode a Vpx protein if it leads to a stronger induction of an immune response and not HIV1? In humans, HIV-1 and HIV-2 are very recent viruses, but the corresponding simian viruses have co-evolved with their simian hosts for a very large period of time and are not generally considered highly pathogenic. This co-evolution has allowed the viruses to select for features that balance an optimal replication with minimal pathogenesis. This results not only from limiting the intrinsic replication capacity of the virus, but also from a sufficient susceptibility to the immune response. In agreement with this concept, it was suggested that while the SIV lineage of HIV-2 encodes Vpx to abrogate SAMHD1, the lentiviral SIV lineage that gave rise to HIV-1 lacks Vpx and must have selected for other features that collectively achieved successful replication without advert pathogenesis [51]. It is likely that the moderate induction of an adapted immune response through other means than Vpx was among these features of the HIV-1 ancestors in simian hosts. We propose that this adaptation feature might have been lost during zoonosis to human, giving rise to the pathogenic HIV-1. In contrast, HIV-2 has maintained Vpx and its ability to degrade SAMHD1 after its zoonosis to humans [51]. This offers a plausible contribution to explain the reduced pathogenicity of HIV-2, in addition to other differences [49,52]. In fact, many viruses, including chronic viruses that induce an immune response and persist in the host, replicate in antigen-presenting cells including dendritic cells [53–58] and, beyond viruses, many bacteria replicate preferentially in the closely related macrophages [59]. Overall, we propose that HIV-2 induces a form of immune tolerance through infection of dendritic cells, while HIV-1 is not well tolerated due to (at least) a restricted infection of dendritic cells [60]. Alternatively, we do not exclude that HIV-2 relies on Vpx for an uncharacterized requirement independent of the immune response, such as viral transmission or dissemination in vivo. In that case, induction of an immune response in dendritic cells would be a mere collateral damage, while HIV-1 would not depend on such requirement and/or would have selected for other means to meet this requirement. Along this line, dendritic cells are increasingly recognized as key samplers at mucosal surfaces, and were recently reported to transport HIV-1 particles across an artificial mucosal layer in vitro [61]. We propose that HIV-2 may favor productive infection of dendritic cells for transmission while HIV-1 would preferentially rely on cell-to-cell transmission of captured viral particles by dendritic cells.
Other viral determinants Besides capsid, HIV-1 Gag contains matrix, nucleocapsid, p6 and short spacer peptides. Nucleocapsid and matrix interact with nucleic acids and could play a role in regulating innate immune sensing pathway. In addition Current Opinion in Virology 2015, 11:55–62
60 Viral pathogenesis
to recruiting Vpx and Vpr, p6 plays an important function in virion morphogenesis, a step in the viral replication cycle that remains unexplored in relation to innate immune sensing pathways. HIV-1 Pol codes for the enzymatic proteins of the virus. Through its role during reverse transcription, the viral reverse transcriptase has an implicit role on innate immune sensing of the viral cDNA. We now need to better understand the range of nucleic acids products that are generated during reverse transcription. It is also possible that additional activities are embedded in RT proteins to modulate innate immune response. In Pol, RNAse H activity could minimize innate sensing of viral RNA species in the cytosol. The viral protease is released during fusion of viruses with cells and could target innate immune signaling proteins, paralleling other viral proteases [62]. Finally, HIV-1 Env, Vif, Nef, Tat and Rev could also play important roles in regulating innate immune sensing pathway. In particular, the transcriptional activity of Tat makes it an attractive candidate for the regulation of innate immune gene expression, which appears to be an emerging theme in the regulation of innate immune response [63].
and ANR-11-LABX-0043), ACTERIA Foundation, Fondation Schlumberger pour l’Education et la Recherche (FSER) and European Research Council grant 309848 HIVINNATE.
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Conclusions HIV-1 has revealed a remarkable ability to escape several host-encoded innate sensing pathways. Identification of these pathways is essential, because they teach us which arms of the immune system are avoided by the virus and that should be accordingly restored by therapeutic or prophylactic approaches. Since these are not normally triggered by the virus, the careful use of engineered, mutated or heterologous viral strains and cells is of paramount importance and should not be viewed as irrelevant artificial situations. In fact, it is the same approach that was and is still used with great success to identify restriction factors. However, while restriction and resistance factors of intrinsic immunity often show a ubiquitous activity in the different target cells of the virus, we discussed how innate sensors and innate immunity show a high degree of cell-type specificity. The quality of the resulting responses is also cell-type specific, and unrestrained or chronic triggering of some innate immune pathways by HIV-1 probably contributes to pathogenesis and chronic immune activation instead of immune protection [64]. This highlights the notion that innate immunity is unlike restriction factors and is not an all-ornone host defense system, but should be rather viewed as a system that tunes viral replication with the immune response. Altogether, innate sensing pathways constitute a fascinating framework where viral replication is directly connected to the immune system.
Acknowledgements We apologize to authors and colleagues whose work was not cited. We thank Philippe Benaroch for critical reading. This work was supported by ATIP-Avenir program, Agence Nationale de Recherche sur le SIDA (ANRS), Ville de Paris Emergence program, European FP7 Marie Curie Actions, LABEX VRI, LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* Current Opinion in Virology 2015, 11:55–62
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42. Galao RP, Le Tortorec A, Pickering S, Kueck T, Neil SJ: Innate sensing of HIV-1 assembly by Tetherin induces NFkappaBdependent proinflammatory responses. Cell Host Microbe 2012, 12:633-644. Demonstrates that tetherin functions as an innate immune sensor of membrane-tethered viral particles.
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ScienceDirect Viral and cellular mechanisms of the innate immune sensing of HIV Xavier Lahaye1,2 and Nicolas Manel1,2 HIV-1 replicates in immune cells that normally respond to incoming viruses and induce antiviral immune responses. Under this constant surveillance, how HIV-1 interacts with the host to escape immune control and causes immunopathology is still being untangled. Recently, a series of HIV-1 interactions with innate sensors of viruses expressed by immune target cells have been identified. Here, we review the HIV-1 factors that escape, engage and regulate these innate immune sensors. We discuss the general principles of these interactions as well as the remarkable cell-type specificity of the regulatory mechanisms and their resulting immune responses. Innate sensors directly intersect viral replication with immunity, and understanding their triggering, or lack thereof, improves our ability to design immune interventions. Addresses 1 Institut Curie, 12 rue Lhomond, 75005 Paris, France 2 INSERM U932, 12 rue Lhomond, 75005 Paris, France Corresponding author: Manel, Nicolas ([email protected])
Current Opinion in Virology 2015, 11:55–62 This review comes from a themed issue on Viral pathogenesis Edited by Matteo Iannacone and Luca Giudotti
http://dx.doi.org/10.1016/j.coviro.2015.01.013 1879-6257/# 2015 Elsevier Ltd. All rights reserved.
Introduction While HIV-1 induces an immune response in the infected host, this response is unable to sterilize infection and generally poor at controlling viral replication, leading to AIDS. The tropism for HIV-1 to immune cells suggests that viral replication in the immune system disables it, which leads to AIDS-induced pathogenesis [1]. However, how HIV-1 escapes protective immunity in a host that is initially immunocompetent is still unresolved. Furthermore, what are the processes of viral replication that lead to immunodeficiency remains a disputed question. In the recent year, the identification of HIV-1 interactions with the innate immune system has provided fresh views on these two important problems. At the core of the innate immune system are innate immune sensing pathways, which consist of non-clonal processes that relay changes in host state to immunity. In the context of HIV-1, these www.sciencedirect.com
changes can be directly induced by the virus, as well as indirectly through tissue damages and disruptions of cellular integrity, for example. Here, we will review the main implications of HIV-1 proteins and nucleic acids in innate immune sensing and the underlying cellular and molecular mechanisms.
Viral nucleic acids Sensing of viral nucleic acids by TLRs
The HIV viral particles contain two copies of the viral genome as ssRNA. TLRs constitute the first line of sensors encountered by HIV in the form of exogenous viral particles. Among all TLRs, TLR7 and TLR8 have the capacity to recognize the genomic ssRNA of HIV [2] (Table 1). Recognition of the HIV-1 ssRNA has been best analyzed in plasmacytoid dendritic cells (pDCs) thanks to the rapid and strong production of type I interferon that ensues [3]. In pDCs, recognition is mediated by TLR7 [4], occurs in an endosomal compartment [5,6], does not require productive viral replication [6] and leads to the production of IFNa and TNFa [5]. Recognition of the HIV-1 RNA by TLR7 and TLR8 has also been observed in monocytes and monocyte-derived dendritic cells (MDDCs). In monocytes, it has been shown that recognition of the HIV-1-derived ssRNA by TLR7 and TLR8 leads to production of IL6 and TNFa in one study [7], while infection of monocytes by HIV-1 was proposed to induce inflammasome activation but not production of IFNs in other studies [8,9]. In MDDCs, in contrast, it has been proposed that recognition of the HIV-1 RNA by TLR7 and TLR8 signals to increase subsequent viral transcription and hence viral production by the cells and no immune response was reported [10]. Finally, it was recently proposed that TLR7 expression in CD4+ T cells is functional for recognition of the HIV-1 RNA [11]. The outcome is complex as it induces simultaneously anergy of the T cells and an increase in viral production. The viral particles contain also additional nucleic acids, such as the cell-derived tRNA used for priming reverse transcription, and there putative recognition by TLRs remains an intriguing possibility. Overall, the viral genome in viral particles has clearly emerged as an important viral nucleic acid for TLR activation. After viral fusion with the cell, HIV-1 particles release their capsid in the cytosol, which contains the viral ssRNA. It is reverse transcribed in viral cDNA, which is transported to the nuclear genome for integration. During these processes, the virus-derived nucleic acids that are generated are putative triggers for innate immune Current Opinion in Virology 2015, 11:55–62
56 Viral pathogenesis
Table 1 Viral factors in HIV-1 that are directly recognized by innate sensors Viral factor ssRNA in the particle
Viral dsDNA and related RT products
Innate sensor
Refs
TLR7 in pDCs
Type I IFN
[2 ,3,5]
TLR7 and TLR8 in monocytes
IL1b, IL6 and TNFa
[7–9]
cGAS recognition in MDDCs
Type I IFN and activation of antigen presentation when SAMHD1 is abrogated Type I IFN when CypA or CPSF6 are inhibited Type I IFN when TREX1 is absent IL1b and pyroptosis; type I IFN
[20,21]
Type I IFN
[15]
Inflammatory cytokines production
[42,43]
Unknown sensor in MDMs cGAS in TREX1-deficient MDMs IFI16 in tonsilar CD4+ T cells recognition Unknown sensor in SLX4-inhibited cell lines Membrane-tethered viral particles
Innate immune response to the viral component
Tetherin
sensors. These include potentially a wide range of nucleic acid species: dsDNA, structured ssRNA, short ssDNA, linear ssRNA, hybrids RNA:DNA and degradation or modified products. In the past years, a series of studies have described that HIV-derived DNA species can activate cytosolic innate sensors [12,13,14,15,16] (Table 1). Sensing of cytosolic viral nucleic acids in dendritic cells
In MDDCs, HIV-1 infection does not normally induce an innate immune response (Figure 1a) [12,17]. Bypassing the SAMHD1 restriction [18,19] upon infection with the viral Vpx protein (see below for the role of Vpx) leads to production of type I interferon and innate immune activation (Figure 1b). Accordingly, HIV-2, which naturally encodes Vpx, also induces this response. In HIV-2, it requires the presence of the viral cDNA in the cytosol, but does not require nuclear entry of the genome and viral integration (Figure 1c). In HIV-1, activation further requires integration and expression of newly synthesized capsid [12] (see below for the role of capsid) (Figure 1b). In both cases, the DNA sensor cyclic GMP–AMP synthase (cGAS) is required, a sensor that produces the second messenger cyclic GMP–AMP (cGAMP) [20,21]. cGAMP has a high affinity for STING, an ER-resident protein, and its binding to STING induces the recruitment of a signaling machinery that ultimately leads to activation of IRF3. The requirement for cGAS indicates that the cytosolic viral cDNA is required for sensing in the case of HIV-1, even if the incoming viral capsid is not permissive. Overall, the viral cDNA is thus essential for innate sensing of the virus, but it is constrained by the viral capsid context: depending on its amino acid sequence and interaction with cofactors (see below), the viral capsid has the ability to either shield the viral cDNA away from innate sensors or favor the viral cDNA access to sensors. HIV-1 can replicate to some extent in DCs when SAMHD1 is active (in the absence of Vpx) leading to a Current Opinion in Virology 2015, 11:55–62
[22] [14,20] [16,23,64]
significant fraction of infected cells. However, this does not trigger an innate immune response and sensing requires alleviation of SAMHD1 restriction [12]. Even with Vpx, it is not necessarily all the infected cells at a given rate of infection that trigger an innate immune response [12]. Here, it should be noted that SAMHD1 impacts the efficiency of reverse transcription in the cytosol and that the frequency of infected cells (as indicated by viral or reporter protein expression) does not necessarily reflect the total amount of viral cDNA in the cytosol. At a given frequency of infected cells, it is likely that cells without SAMHD1 contain a much larger pool of cytosolic cDNA sufficient to activate cGAS, whereas in the presence of SAMHD1, the quantity of cytosolic viral cDNA produced does not reach a sufficient threshold to trigger cGAS. The relative abundance of these cytosolic pools may not necessarily relate to the infection rate of the cell. Indeed, it is very likely that several steps after reverse transcription are saturable and/ or that not all RT products are competent for transport to the nucleus and integration. When considering these innate immune sensing pathways, it is essential to consider the relevant viral material (e.g. the amount of cytosolic viral cDNA and the capsid), and not only the apparent infection rate of the cells. Sensing of cytosolic viral nucleic acids in CD4+ T cells and macrophages
In monocyte-derived macrophages (MDMs) and CD4+ lymphocytes, HIV-1 infection proceeds and does not normally induce detectable type I interferon production [14,22] (Figure 1d). However, in the absence of TREX1, a DNA exonuclease, HIV-1 infection induces a type I interferon response [14]. It is thought that TREX1 normally degrades by-products of the viral reverse transcription process, and these products accumulate in the absence of TREX1, leading to innate sensor activation. The response in TREX1-deficient cells requires the DNA sensor cGAS [20] as well as STING, TBK1 and IRF3. In addition to TREX1-deficient cells, www.sciencedirect.com
HIV sensing in innate immunity Lahaye and Manel 57
Figure 1
Monocyte-derived dendritic cells HIV-1
(a)
(b) HIV-1, with Vpx
CypA
Monocyte-derived macrophages HIV-2
(c)
HIV-1, with inhibition of (e) CypA or CPSF6
HIV-1
(d)
CypA
CypA
CPSF6
dNs
cGAS
cGAS
VPX
cGAS
VPX
dNTPs
dNs
cGAS
dNTPs SAMHD1
SAMHD1
cGAS ?
dNs dNTPs SAMHD1
Integrated proviral DNA
Current Opinion in Virology
Cytosolic sensing of HIV in monocyte-derived macrophages and monocyte-derived dendritic cells. For clarity, the impact of the innate immune responses on viral replication and on the other cells of the immune system is not depicted. (a) In MDDCs, HIV-1 infection is highly restricted by SAMHD1 and does not trigger an interferon response or dendritic cell activation. (b) When SAMHD1 is abrogated with Vpx, HIV-1 infects efficiently the MDDCs and triggers an innate immune response through cGAS. The incoming viral capsid initially shields viral DNA sensing by cGAS. Newly synthesized capsid production after viral integration and interaction with CypA (depicted as Gag bound to CypA) is required to render the viral DNA susceptible to sensing by cGAS. (c) HIV-2 abrogates SAMHD1 after viral entry leading to an efficient infection of the cells and to induction of an innate immune response. In contrast to HIV-1, the incoming capsid is permissive for sensing of the viral cDNA by cGAS before nuclear entry and integration. (d) In MDMs, HIV-1 infection does not trigger innate sensors. Although infection is presumably less restricted than in MDDCs by SAMHD1, the capsid interacts with CypA and CPSF6 and prevents innate sensor activation. (e) When CypA or CPSF6 are inhibited, the capsid is permissive and HIV-1 induces a type I interferon response triggered by the viral DNA. cGAS is a suspected sensor for this response.
induction of IFN by HIV-1 was reported in MDMs when interaction of the viral capsid with host factors was perturbed (see below for the role of capsid) [22]. In this setting, sensing also requires reverse transcription and the production of cGAMP was detected, suggesting that cGAS is also implicated and recognizes the viral cDNA. How this sensing occurs despite the presence of functional TREX1 is not understood. Finally, in CD4+ T cells from tonsil, sensing of abortive reverse transcription leads to induction of caspase-1-dependent pyroptosis. In these cells, the DNA sensor IFI16 binds to the viral DNA and is required for induction of pyroptosis [16,23].
is capped and polyA-tailed, alike host messenger RNAs, which may contribute to the lack of responses. Additionally, it remains possible that a TREX1-like activity against viral ssRNA, such as SKIV2L, may prevent such response [24]. Summarizing, in the cytosol, the products of reverse transcription constitute various substrates for the innate immune sensors cGAS and IFI16. The resulting immune responses are diverse and show a high level of cell-type specificity, but still need to be further characterized (Table 1).
In contrast to reverse transcription products, the incoming viral ssRNA has not been reported to trigger innate immune sensing pathways. The genomic RNA of HIV
Several studies have shown that the viral capsid protein is a key regulatory factor of innate sensing pathway through its binding to host factors (Table 2).
Viral capsid protein and capsid-interacting proteins
Table 2 Viral proteins that interact with host factors and regulate innate sensing Viral protein
Interacting host factor
Impact on innate sensing
Refs.
Capsid in Gag
CypA in MDDCs CypA in MDMs CPSF6 in MDMs TRIMCyp in simian cells
Promotes cGAS-dependent sensing of viral DNA Prevents innate sensing of viral DNA Prevents innate sensing of viral DNA Inflammatory cytokines
[12,21] [22] [22] [39]
Vpu Vpr Vpx
Tetherin SLX4 SAMHD1 in MDDCs
Prevents sensing of membrane-tethered viral particles Prevents innate sensing of viral DNA Promotes innate sensing of viral DNA
[42,43] [15] [12,21]
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58 Viral pathogenesis
Capsid and CypA
Cyclophilin A (CypA), a peptididyl prolylisomerase, is the first host protein shown to directly bind to the viral capsid on a loop in the N-terminal domain [25]. CypA is incorporated into viral particles [26,27]. Loss of interaction, by Cyclosporin A treatment or silencing leads to a reduction of HIV infectivity due to a block in replication in several but not all cell types, indicative that CypA can promote HIV-1 infectivity and replication, although the underlying mechanism has still not been resolved [25,26]. In MDDCs and MDMs, innate sensing of the HIV-1 cDNA is regulated by capsid and its interactions with CypA, and the HIV-1 capsid normally prevents premature innate immune sensing of the viral cDNA before integration (Figure 1a,d) but there are key differences. In MDDCs with Vpx, the HIV-1 capsid prevents innate immune sensing of the viral cDNA before integration, and sensing is triggered when newly synthesized capsid is produced after viral integration and expression [12] (Figure 1b). This sensing of HIV-1 by MDDCs requires CypA binding to capsid. In MDMs, sensing is in contrast prevented by CypA (Figure 1d) and, when CypA binding to capsid is abrogated, sensing occurs before nuclear entry and despite the presence of SAMHD1 and TREX1 [22] (Figure 1e). In MDDCs, a comparable inhibition of CypA does not lead to induction of interferon after infection with HIV-1 by itself [12]. Thus, CypA regulates innate sensing in a cell-type specific manner, with opposite outcomes in MDMs versus MDDCs. This may not be a surprise, given the well-recognized cell-type specific role of CypA in infection [28]. In MDDCs, the analysis of innate sensing was extended to HIV-2, which naturally contains Vpx (Figure 1c) [12]. Sensing of HIV-2 also requires Vpx, cGAS and the viral cDNA. In contrast to HIV-1, HIV-2 capsid binds weakly CypA and it is permissive to sensing of the viral cDNA before integration, while simultaneously allowing nuclear entry and productive viral infection (Figure 1c) [21]. In both HIV-1 and HIV-2, increasing the affinity of the capsids to CypA renders the capsid strongly favorable for innate sensing of the viral cDNA and concurrently much less capable at leading to a productive viral infection [21]. Overall, HIV-1 has evolved to minimize triggering of innate DNA sensors in dendritic cells and macrophages, through a combination of a limited reverse transcription in these cells (due to SAMHD1) and an optimal capsid protein in interaction with CypA.
capsid is required to prevent premature sensing of the viral cDNA (Figure 1d). Abrogating CPSF6 expression or its binding to capsid (N74D mutation in capsid) allows HIV-1 to induce an interferon response in MDMs [22] (Figure 1e). Thus, CPSF6 plays an analogous role to CypA in this model. It was speculated that these factors prevent premature reverse transcription in macrophages in a way that prevents innate sensing, although it remains unclear how timing of reverse transcription can influence the fate of the viral cDNA. Other capsid interacting factors
The HIV viral capsid has been reported to interact biochemically or genetically with a wealth of other factor, including TRIM5a, MX2, TNPO3, NUP153, RANBP2. Among them, MX2 is an IFN-inducible resistance gene that has antiviral activity against HIV-1 [33–35]. MX2 targets incoming virus in a CypA-dependent manner and inhibits the viral DNA nuclear import [33–35]. Interestingly, MX2 localizes to the cytoplasmic side of nuclear pores and has been suggested to regulate nucleocytoplamic transport [36]. It is thus tempting to speculate that MX2 activity may impact innate immune sensing pathways of the viral cDNA. TRIM5a has been linked to the regulation of LPS signaling and can function as a sensor for capsid lattice of retroviruses, but human TRIM5a does not bind to the HIV-1 capsid [37,38] and thus unlikely behaves as an HIV-1 sensor in human cells [39]. Overall, it will be important to examine the putative contribution of these factors to innate immune sensing pathways. To summarize, the HIV-1 capsid has emerged as a major determinant of the fate of the viral cDNA toward innate immune sensors, at least in myeloid target cells. It is likely that the intrinsic stability of the capsid has a major role in preventing exposure of the viral cDNA to sensors before its entry into the nucleus. In addition, the binding of host factors to capsid determines the fate of the cDNA. Intriguingly, CypA appears to function differently in MDMs vs. MDDCs. This may result at least from a differential role of SAMHD1 or from other capsid-interacting factors.
Accessory proteins HIV encodes accessory proteins that regulate specific aspects of the viral replication. Among them, Vpu and Vpr in HIV-1, and the closely related Vpx in HIV-2/ SIVmac have emerged as key regulators of the interaction of HIV with the innate sensors (Table 2).
Capsid and CPSF6
Cleavage and polyadenylation specific factor 6 (CPSF6) is a nuclear host protein that binds the viral capsid adjacently to the CypA binding loop [29,30]. CPSF6 is actively transported to the nucleus by TNPO3, which appears to be the main function of TNPO3 in the viral cycle [31,32]. In MDMs, it was shown that CPSF6 binding to Current Opinion in Virology 2015, 11:55–62
Vpu
Vpu antagonizes the restriction enforced by Tetherin on viral release [40,41]. In the absence of Vpu, Tetherin also functions as an innate immune sensor triggered by the cell surface retention of viral particles [42]. The physical clustering of Tetherin by trapped viral particles www.sciencedirect.com
HIV sensing in innate immunity Lahaye and Manel 59
induces NF-kB signaling that induces expression of proinflammatory cytokines CXCL10, IL6 and IFNb [42,43]. Release of cytokines by cells infected with a Vpu-defective virus confers an antiviral state to bystander cells [43]. It will be important to determine to what extent this release of cytokines may contribute to shaping the innate and adaptive immune response during the infection. Vpr
Vpr was recently implicated in the regulation of innate immunity through its binding to the SLX4 protein [15], a coordinator of endonucleases normally implicated in the resolution of DNA structures generated during DNA replication and repair, such as Holliday junctions. Vpr directly binds to both SLX4 and VPRBP, an E3-ubiquitin ligase. This combined recruitment leads to the enhancement of the endonuclease activity of MUS81 and EME1, the endonucleases normally regulated by SLX4. In HeLa cells, depleting SLX4, VPRBP or MUS81 expression leads to an increase in type I interferon expression independently of viral infection, indicating that these proteins are negative regulators of an endogenous production of type I interferon [15]. In addition, infection of HeLa cells with a virus defective for Vpr leads to a small increase in type I interferon and MxA expression, as well as an increase in the total amount of viral DNA in the cell. Furthermore, the viral DNA interacts with SLX4 in the presence of Vpr [15]. This suggests that Vpr-mediated activation of the SLX4 complex plays a role similar to TREX1 in limiting the pool of viral DNA available to cytosolic sensors. Intriguingly, the magnitude of interferon induction in HeLa cells in the absence of Vpr is small. It is plausible that TREX1 and capsid contribute to this limited interferon induction detected in the absence of Vpr in Hela cells, and it will be important to establish the status of this pathway in primary target cells of the virus. Vpx
SAMHD1 restricts HIV-1 replication in myeloid cells [18,19] and resting CD4+ T cells [44,45]. HIV-1 does not encode a protein to abrogate the SAMHD1 restriction. In contrast, the related virus HIV-2 encodes the Vpx protein, closely related to Vpr, that recruits SAMHD1 and VPRBP, leading to degradation of SAMHD1. SAMHD1 is an Aicardi-Goutie`res syndrome gene [46] that functions as a dNTP hydrolase [47] and possibly as a RNA endonuclease to limit HIV replication at the level of reverse transcription [48]. In MDDCs, Vpx is required for type I interferon induction and activation of antigen presentation by HIV-1 (by way of complementation) and by HIV2. We previously described the role of the viral DNA and capsid in this induction. Intriguingly, HIV-2 is less pathogenic than HIV-1 presumably due to a contribution of a more effective immune response [49,50]. This led to the hypothesis that induction of an innate immune response by HIV-2, and its lack thereof in HIV-1, could contribute the better outcome of HIV-2 infection. www.sciencedirect.com
Why HIV-2 would encode a Vpx protein if it leads to a stronger induction of an immune response and not HIV1? In humans, HIV-1 and HIV-2 are very recent viruses, but the corresponding simian viruses have co-evolved with their simian hosts for a very large period of time and are not generally considered highly pathogenic. This co-evolution has allowed the viruses to select for features that balance an optimal replication with minimal pathogenesis. This results not only from limiting the intrinsic replication capacity of the virus, but also from a sufficient susceptibility to the immune response. In agreement with this concept, it was suggested that while the SIV lineage of HIV-2 encodes Vpx to abrogate SAMHD1, the lentiviral SIV lineage that gave rise to HIV-1 lacks Vpx and must have selected for other features that collectively achieved successful replication without advert pathogenesis [51]. It is likely that the moderate induction of an adapted immune response through other means than Vpx was among these features of the HIV-1 ancestors in simian hosts. We propose that this adaptation feature might have been lost during zoonosis to human, giving rise to the pathogenic HIV-1. In contrast, HIV-2 has maintained Vpx and its ability to degrade SAMHD1 after its zoonosis to humans [51]. This offers a plausible contribution to explain the reduced pathogenicity of HIV-2, in addition to other differences [49,52]. In fact, many viruses, including chronic viruses that induce an immune response and persist in the host, replicate in antigen-presenting cells including dendritic cells [53–58] and, beyond viruses, many bacteria replicate preferentially in the closely related macrophages [59]. Overall, we propose that HIV-2 induces a form of immune tolerance through infection of dendritic cells, while HIV-1 is not well tolerated due to (at least) a restricted infection of dendritic cells [60]. Alternatively, we do not exclude that HIV-2 relies on Vpx for an uncharacterized requirement independent of the immune response, such as viral transmission or dissemination in vivo. In that case, induction of an immune response in dendritic cells would be a mere collateral damage, while HIV-1 would not depend on such requirement and/or would have selected for other means to meet this requirement. Along this line, dendritic cells are increasingly recognized as key samplers at mucosal surfaces, and were recently reported to transport HIV-1 particles across an artificial mucosal layer in vitro [61]. We propose that HIV-2 may favor productive infection of dendritic cells for transmission while HIV-1 would preferentially rely on cell-to-cell transmission of captured viral particles by dendritic cells.
Other viral determinants Besides capsid, HIV-1 Gag contains matrix, nucleocapsid, p6 and short spacer peptides. Nucleocapsid and matrix interact with nucleic acids and could play a role in regulating innate immune sensing pathway. In addition Current Opinion in Virology 2015, 11:55–62
60 Viral pathogenesis
to recruiting Vpx and Vpr, p6 plays an important function in virion morphogenesis, a step in the viral replication cycle that remains unexplored in relation to innate immune sensing pathways. HIV-1 Pol codes for the enzymatic proteins of the virus. Through its role during reverse transcription, the viral reverse transcriptase has an implicit role on innate immune sensing of the viral cDNA. We now need to better understand the range of nucleic acids products that are generated during reverse transcription. It is also possible that additional activities are embedded in RT proteins to modulate innate immune response. In Pol, RNAse H activity could minimize innate sensing of viral RNA species in the cytosol. The viral protease is released during fusion of viruses with cells and could target innate immune signaling proteins, paralleling other viral proteases [62]. Finally, HIV-1 Env, Vif, Nef, Tat and Rev could also play important roles in regulating innate immune sensing pathway. In particular, the transcriptional activity of Tat makes it an attractive candidate for the regulation of innate immune gene expression, which appears to be an emerging theme in the regulation of innate immune response [63].
and ANR-11-LABX-0043), ACTERIA Foundation, Fondation Schlumberger pour l’Education et la Recherche (FSER) and European Research Council grant 309848 HIVINNATE.
References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest 1. 2.
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Conclusions HIV-1 has revealed a remarkable ability to escape several host-encoded innate sensing pathways. Identification of these pathways is essential, because they teach us which arms of the immune system are avoided by the virus and that should be accordingly restored by therapeutic or prophylactic approaches. Since these are not normally triggered by the virus, the careful use of engineered, mutated or heterologous viral strains and cells is of paramount importance and should not be viewed as irrelevant artificial situations. In fact, it is the same approach that was and is still used with great success to identify restriction factors. However, while restriction and resistance factors of intrinsic immunity often show a ubiquitous activity in the different target cells of the virus, we discussed how innate sensors and innate immunity show a high degree of cell-type specificity. The quality of the resulting responses is also cell-type specific, and unrestrained or chronic triggering of some innate immune pathways by HIV-1 probably contributes to pathogenesis and chronic immune activation instead of immune protection [64]. This highlights the notion that innate immunity is unlike restriction factors and is not an all-ornone host defense system, but should be rather viewed as a system that tunes viral replication with the immune response. Altogether, innate sensing pathways constitute a fascinating framework where viral replication is directly connected to the immune system.
Acknowledgements We apologize to authors and colleagues whose work was not cited. We thank Philippe Benaroch for critical reading. This work was supported by ATIP-Avenir program, Agence Nationale de Recherche sur le SIDA (ANRS), Ville de Paris Emergence program, European FP7 Marie Curie Actions, LABEX VRI, LABEX DCBIOL (ANR-10-IDEX-0001-02 PSL* Current Opinion in Virology 2015, 11:55–62
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