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. Author manuscript; available in PMC: 2016 May 16.
Published in final edited form as: Curr Opin Struct Biol. 2015 May 16;31:106–114. doi: 10.1016/j.sbi.2015.04.004

HIV Suppression by Host Restriction Factors and Viral Immune Evasion

Xiaofei Jia 1, Qi Zhao 1, Yong Xiong 1,✉
PMCID: PMC4476947  NIHMSID: NIHMS691147  PMID: 25939065

Abstract

Antiviral restriction factors are an integral part of the host innate immune system that protects cells from viral pathogens, such as human immunodeficiency virus (HIV). Studies of the interactions between restriction factors and HIV have greatly advanced our understanding of both the viral life cycle and basic cell biology, as well as provided new opportunities for therapeutic intervention of viral infection. Here we review the recent developments towards establishing the structural and biochemical bases of HIV inhibition by, and viral countermeasures of, the restriction factors TRIM5, MxB, APOBEC3, SAMHD1, and BST2/tetherin.

Introduction

The host innate immune system has a diverse array of antiviral responses, including intrinsic antiviral proteins termed restriction factors that inhibit distinct stages of the viral life cycle. The last decade of HIV research has seen the discovery of many anti-HIV restriction factors that blocks the infection at steps including capsid uncoating (TRIM5), reverse transcription (APOBEC3 and SAMHD1), nuclear import and integration (MxB), translation (Schlafen 11), and budding (BST2/Tetherin) (Figure 1). Some of these restriction factors also trigger broad innate immune signaling for further viral suppression. The virus, in turn, has developed an arsenal of methods to evade the host defense. HIV counteracts or avoids some of these restriction factors either by using antagonistic accessory proteins (Vif, Vpu, Vpx/Vpr, Nef, etc.) or by mutating protein interfaces. Studying the ongoing arms race between HIV and the host greatly advances our understanding of the viral life cycle and the human immune system, while simultaneously providing new avenues for therapeutic intervention.

Figure 1. Host restriction factors that inhibit various stages of the HIV life cycle.

Figure 1

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HIV particles are shown as gray circles with envelop glycoproteins coated on the outside and a cone (trapezoid)-shaped capsid inside. Capsid protein hexamers are shown as black hexagons. Green curvy lines represent viral RNA and red curvy lines viral DNA. Restriction factors are illustrated in various shapes with the periphery highlighted in yellow and with their functions labeled.

A first line of defense: Retrovirus capsid pattern sensing by TRIM5 proteins

The tripartite motif 5 (TRIM5) proteins, including TRIM5α and TRIMCyp, directly recognize the retroviral capsid in a species-specific manner [1,2]. TRIM5 proteins elicit premature disassembly of the capsid and activate cellular innate immune signaling pathways [3]. The conserved N-terminal tripartite motif of TRIM5 proteins consists of a RING domain (E3 ligase activity), a B-box domain (higher-order oligomerization), and a coiled-coil domain (dimerization) (Figure 2A). The C-terminal PRY/SPRY (TRIM5α) or CypA (TRIMCyp) domain confers capsid binding and specificity. Functioning as a viral capsid pattern sensor, TRIM5α binds only to the assembled hexameric capsid lattice [4]. Interestingly, although the global capsid pattern is the binding determinant, TRIM5α has an ability to interact with retroviral capsids of diverse shapes and curvatures.

Figure 2. Structural insights for the antiviral mechanisms of TRIM5α and MxB.

Figure 2

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(A) Domain organization of rhesus TRIM5α or TRIMCyp. (B) The crystal structure of the PRY/SPRY domain of rhesus TRIM5α (PDB ID: 4B3N) in ribbon presentation, with the variable loops in yellow. The unobserved portion of the V1 loop is illustrated as a dotted line. (C) Overlay of the crystal structures of the TRIM25 coiled-coil domain (yellow, PDB ID: 4LTB) and the rhesus TRIM5α B-box (blue) and coiled-coil (cyan) domain (PDB ID: 4TN3). (D) Two orthogonal views of a model of the rhesus TRIM5α structure containing the B-box, coiled-coil, and PRY/SPRY domains. The PRY/SPRY (PDB ID: 4B3N) and the B-box and coiled-coil (PDB ID: 4TN3) domains were positioned together by overlaying a six-amino acid region present in both structures. (E) Model of the lattice of rhesus TRIM5α (ribbon representation, without the ring domain) formed on top of the HIV capsid lattice (hexagonal grid). TRIM5α and the capsid lattice are drawn to the same scale based on the observed dimensions. (F) Domain organization of MxB. (G) The MxB (orang, blue, and yellow, PDB ID: 4WHJ) and MxA (gray, PDB ID: 3SZR) structures overlaid based on the BSE domains. (H) The MxB dimer in surface representation. Regions in MxA (circles) and MxB (ovals) responsible for viral recognitions are located at the opposite side of the dimer. (I) Model of MxB dimer binding to the capsid lattice (hexagonal grid). MxB and the capsid lattice are drawn to the same scale based on the observed dimensions.

Crystal structures of the rhesus macaque TRIM5α PRY/SPRY domain provided the first insight into the potential mode of interaction between TRIM5α and the viral capsid. The structures show a core of two antiparallel β sheets with one side of the molecule displaying flexible variable loops that are critical for capsid binding (Figure 2B) [5•,6•]. Rhesus TRIM5α, but not human TRIM5α, recognizes and restricts HIV-1, although a single mutation (R332P) in the variable loop 1 of the human PRY/SPRY domain confers HIV-1 capsid binding and restriction [7-9]. Modeling of the TRIM5α PRY/SPRY domain onto the capsid lattice suggests that the flexibility provided by the variable loops may enable TRIM5α to recognize retroviral capsids with a variety of curvatures [6•].

The TRIM5 B-box and coiled-coil domains mediate higher-order self-association that enables avid binding to retroviral capsid cores, as monomeric TRIM5 domains bind capsid weakly. A TRIM5-TRIM21 chimera (TRIM5-21R) has been observed by electron microscopy to form a two-dimensional hexagonal lattice on the surface of a preassembled HIV-1 capsid lattice [10]. The crystal structures of the coiled-coil region of TRIM25 and the B-box-coiled-coil region of TRIM5α provided insights into TRIM5 dimerization and lattice assembly [11•,12•] (Figure 2C). The coiled-coil region of TRIM proteins adopts an antiparallel conformation, with a downstream α-helix folding back in a hairpin-like manner to bring the capsid-binding modules near the midpoint of the coiled-coil (Figure 2D). The length of the coiled-coil (17 nm) matches the dimension of the observed TRIM5-21R hexagonal lattice. The TRIM5α B-box domains sit at opposite ends of the coiled-coil. This configuration suggests that within the TRIM5 lattice the B-box domains locate at three-fold symmetry axes, while each PRY/SPRY or CypA pair reside at the center of a hexagonal edge for viral capsid interaction (Figure 2E).

Structural studies of more complete TRIM5 constructs containing the coiled-coil and additional domains (RING, PRY/SPRY or CypA) are needed to further understand TRIM5 architecture. More importantly, the most intriguing and challenging questions remain: what is the structural basis of capsid lattice recognition and disruption by TRIM5α, and how does this recognition lead to downstream immune responses? Answering these questions will likely require innovative approaches to reconstitute the lattice interactions in a form amenable for biochemical and structural biology studies.

HIV restriction by myxovirus resistance protein 2 (MxB)

Human MxB is an interferon-induced restriction factor, which was recently discovered to target HIV-1 [13-15]. Evidence suggests it acts between reverse transcription and integration, and likely interacts with the viral capsid [13-17]. MxB is highly homologous to the well-studied MxA (63% identity) that inhibits influenza-like viruses. Both MxA and MxB are dynamin-like GTPases that contain three domains: GTPase, bundle signaling element (BSE), and stalk (Figure 2F). The recent crystal structure of MxB shows an MxA-like extended anti-parallel dimer [18••]. The relative orientations of the structurally homologous domains are different in the two proteins (Figure 2G), although the functional significance of this difference is currently unclear.

The antiviral mechanism of MxB is distinct from that of MxA. MxB, but not MxA, contains a nuclear localization signal (NLS), which is critical for HIV-1 restriction [14]. The anti-HIV-1 function of MxB is independent of the transfer of information between the GTPase and the stalk domains through hinge regions surrounding the BSE domain [18••]. This is consistent with data showing that MxB antiviral function is independent of GTPase activity [13,14]. Both BSE hinge communication and GTPase activity are critical for MxA antiviral functions. In addition, higher-order oligomerization is required for the antiviral activity of MxA but not MxB [18••]. Strikingly, the viral interaction modules of MxA and MxB appear to lie on the opposite faces of the dimer structures (Figure 2H).

MxB binds to HIV-1 capsid assemblies, but not to capsid protein (CA) hexamers, indicating that MxB may function as another viral capsid pattern sensor (Figure 2I) [18••]. The MxB regions critical for antiviral function, such as the N-terminus and the dimerization interface, are also important for capsid binding. Intriguingly, MxB also interacts with CA mutants that evade MxB restriction in vivo, indicating capsid binding by MxB may be necessary but not sufficient for HIV-1 restriction [18••]. The current data suggest that MxB may restrict HIV-1 infection by interfering with viral nuclear import. However, much remains to be uncovered to explain the detailed mechanism of this newly discovered restriction factor.

Mutation of viral DNA by APOBEC3 proteins

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) is the first cellular protein discovered with intrinsic anti-HIV activity, which marks the beginning of research on HIV restriction factors [19]. A3G is packaged into assembling virions and upon infection of target cells causes dC to dU mutations on the newly reverse transcribed minus strand of viral DNA [20,21]. A3G also restricts HIV by residing on the viral RNA and thereby blocking reverse transcription [22,23]. Antiviral activity is observed for other A3 proteins (A3F/D/H), although to a lesser extent. To evade restriction by the A3 proteins, HIV expresses virion infectivity factor (Vif) to target A3F/G/C for degradation via the host ubiquitin-proteasome pathway [24]. Vif specifically interacts with the cellular cofactor CBFβ and a host E3 ubiquitin ligase that contains the scaffolding protein Cullin 5 (Cul5), the adaptor proteins ElonginB and ElonginC (EloBC), and the E2-linking protein Rbx2. By mimicking the substrate receptor in the multi-component E3 ligase complex, Vif hijacks the ligase to polyubiquitinate A3 proteins.

A3 proteins are cytidine deaminases that contain a primordial Zn2+-coordinating catalytic motif with conserved His-X-Glu and Pro-Cys-X-X-Cys residues (Figure 3A), yet they have different sequence specificity for DNA substrates. The A3G C-terminal domain (CTD) harbors the deaminase activity while the homologous N-terminal domain (NTD) binds DNA/RNA and HIV nucleocapsid for packaging into virions, and contains the target site of HIV Vif. In contrast, the CTD of A3F contains both the deamination and Vif target site. A3G preferentially recognizes a 5′-CCCA-3′ DNA sequence, while A3F prefers 5′–(T/C)TCA-3′ (the deaminated C is underlined). Multiple structures of A3 protein domains have been solved (Figure 3B). The structural findings on the A3 proteins, including the catalytic sites, the predicted DNA-binding regions, and the Vif sensitive regions, have been thoroughly summarized recently in an excellent review [25•] and will not be discussed here. Despite the abundant structural information of apo-proteins, how A3 proteins interact with DNA is still under debate (Figure 3C) [25•], and the molecular determinants that govern the DNA sequence-specific interactions are unknown. These questions can only be addressed unambiguously with structures of appropriate A3 protein-DNA complexes.

Figure 3. Structural bases of the APOBEC3 (deaminase) and SAMHD1 (dNTPase) activities and their antagonization by viral hijacking of host E3 ubiquitin ligase complexes.

Figure 3

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(A) Domain organization of A3G with the catalytic center marked in red and the consensus sequence labeled. (B) Crystal structure of A3G-CTD in ribbon representation with the catalytic residues shown as red sticks and the Zn ion as a gray sphere. (C) Possible DNA binding paths (marked by the rods) on A3G (surface representation). The residues involved in DNA-binding are colored to match the rods. (D) Model of the Vif-E3 ligase based on the structure of the Vif/CBFβ/EloBC/Cul5NTD complex (PDBID: 4N9F). The bound A3 protein target is indicated by an oval. (E) Domain organization of SAMHD1. (F) Crystal structure of SAMHD1 catalytic core tetramer in surface representation (PDB ID: 4TO0) with protomers colored individually. (G) Binding of allosteric GTP/dNTP at a trimeric SAMHD1 interface (boxed), revealed by removing one protomer. Four such GTP/dNTP-binding sites exist in the SAMHD1 tetramer. The bound GTP/dATP and SAMHD1 side chains recognizing the nucleotide bases are shown as sticks and the phosphate-coordinating magnesium ion as a gray sphere (with a bound water molecule as a red sphere). (H) Left: Surface representation of the structure of SIVmnd-2 Vpx (red) in complex with DCAF1-CTD (gray) and the N-terminal region of mandrill SAMHD1 (residues 1-109, light blue) (PDB ID: 5AJA); Right: The structure of SIVsmm Vpx (red) in complex with DCAF1-CTD (gray), and human SAMHD1 C-terminus (residues 606-625, cyan) (PDB ID: 4CC9). (I) Model of the Vpx-E3 ubiqutin ligase targeting SAMHD1, based on the crystal structures of the complexes shown in (H, right structure), the DDB1-DDB2 complex (PDB ID: 3EI3), and the DDB1-Cul4A-Rbx1-SV5V complex (PDB ID: 2HYE).

The structural basis of how HIV Vif targets A3 proteins has not be established, although the recent crystal structure of HIV-1 Vif in complex with CBFβ, EloBC, and Cul5-NTD provided substantial insight into the interactions that enable Vif to hijack the E3 ligase (Figure 3D) [26••]. Notably, Vif engages in extensive contact with the E3 ligase components while keeping residues implicated in A3 binding solvent exposed adjacent to the CBFβ binding site. Interestingly, while HIV-1 Vif directs multiple A3 proteins to the E3 ligase, distinct binding surfaces of Vif are used to antagonize each A3. Accordingly, A3 proteins have different surface regions sensitive to Vif binding. Furthermore, evidence suggests that A3F binding may alter the interaction between CBFβ and Vif [27]. Future structural elucidation showing how A3 proteins are recruited to the Vif-E3 ligase complex will be required to clarify the underlying mechanisms by which Vif antagonizes the APOBEC3 proteins.

Suppression of HIV reverse transcription and regulation of cellular dNTPs by SAMHD1

SAMHD1, a deoxyribonucleoside triphosphate triphosphohydrolase (dNTPase), prevents the infection of blood cells by retroviruses, including HIV, likely by depleting the cellular dNTP pool available for viral reverse transcription [28-30]. In addition, SAMHD1 is ubiquitously expressed in cells of various human tissues [31,32], where it functions in the regulation of cellular dNTP levels, DNA damage signaling, and proper activation of the innate immune response [31,33,34]. Mutations in SAMHD1 are associated with chronic lymphocytic leukemia (CLL) and the autoimmune disease Aicardi-Goutieres syndrome (AGS).

A series of structural and biochemical studies firmly established the mechanism of the dNTPase activity of SAMHD1. The C-terminal catalytic core of SAMHD1 is sufficient to hydrolyze dNTPs and inhibit HIV (Figure 3E). The first crystal structure of the SAMHD1 catalytic core was determined as a dimer without nucleotide bound [30], although its dNTPase activity was found to require a dGTP cofactor. The molecular basis of SAMHD1 activation was subsequently elucidated by determination of crystal structures of the catalytic core in the active, tetrameric conformation (Figure 3F) [35••,36•]. Strikingly, a total of 12 dGTPs bind to the SAMHD1 tetramer, two at each of the four allosteric sites and one at each of the four catalytic sites. The two dGTPs at each allosteric site are non-equivalent (designated as allosteric sites 1 and 2). Binding of the allosteric nucleotides promotes SAMHD1 tetramer formation, which induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme.

Recently, comprehensive structural and enzymatic studies revealed the complete regulatory mechanism of the dNTPase activity of SAMHD1 via combined action of both GTP and dNTPs [37••,38•]. Ji and Tang el al. used 26 GTP/dNTP-bound crystal structures to determine the full spectrum of allosteric and substrate nucleotides bound to SAMHD1 [37••]. Allosteric site 1 strictly selects for GTP (slightly favored) or dGTP, with GTP likely occupying the site in cells due to its much higher cellular concentration (Figure 3G). In allosteric site 2, any type of dNTP, but only a dNTP, can bind with distinct binding affinities. Nonetheless, the rate of catalysis remains relatively constant regardless of which dNTP is bound at allosteric site 2, demonstrating a robust regulatory mechanism of SAMHD1 activity regardless of the identity of the bound dNTPs [37••].

SAMHD1 is counteracted in HIV-2 and related SIVs by the viral proteins Vpx and Vpr [39,40]. Vpx links SAMHD1 to a DDB1/DCAF1-dependent E3 ubiquitin ligase for ubiquitination and proteasomal degradation. Intriguingly, this viral antagonization comes in different flavors as Vpx proteins from different SIV lineages target distinct regions of SAMHD1 and recruit it to the same E3 ligase [41]. The multifaceted targeting mechanisms were elucidated by two recent crystal structures that demonstrated how Vpx molecules target different (N- or C-terminal) tails of SAMHD1 [42••,43••]. One of the two structures consists of a protein complex comprising the human SAMHD1 C-terminus (residues 582-626), the C-terminal domain of DCAF1 (DCAF1-CTD), and the SIVsmm (infecting sooty mangabey monkey) Vpx (Figure 3H,I) [42••]. The second structure illustrated the interactions between the N-terminal region (residues 1-109) of mandrill SAMHD1, DCAF1-CTD, and SIVmnd-2 (SIV infecting mandrill) Vpx (Figure 3H) [43••]. As revealed by the two structures, both of the Vpx lineages co-opt DCAF1 to form a structurally conserved, predefined substrate receptor that has the flexibility to bind either the N- or C-terminal tail of SAMHD1 in a species-specific manner (Figure 3H). DCAF1 and the core of Vpx associate in the same manner in both cases, while the flexible N-terminus of Vpx enables the C-terminal tail of SAMHD1hu to bind to the SIVsmm Vpx-DCAF1 interface, or allows for the N-terminal tail of SAMHD1mnd to be sandwiched between SIVmnd-2 Vpx and DCAF1 (Figure 3H)

Despite the rapid progress, much remains to be learned about SAMHD1. The antiviral activity of SAMHD1 is negatively regulated by phosphorylation at residue T592 [32]. However, the phosphorylation-dependent regulation mechanism is currently unknown and it is under debate whether the phosphorylation-induced loss of the antiviral function of SAMHD1 is due to the reduction of its dNTPase activity. In addition to the dNTPase activity, SAMHD1 also possesses exonuclease activities on single-stranded DNA or RNA substrates [44-46], although the functional relevance of these activities is under investigation. A recent report suggested that the RNase activity of SAMHD1, but not the dNTPase activity, is responsible for HIV restriction [47]. Future studies, including structures of phosphorylated SAMHD1 and SAMHD1 in complex with DNA or RNA, are needed to completely elucidate the mechanisms of antiviral and cellular functions of SAMHD1.

The last line of defense: Enveloped virus tethering by BST2/tetherin

Bone marrow stromal cell antigen 2 (BST2, also named tetherin or CD317) inhibits the release of nascent HIV particles [48,49] and other enveloped viruses by retaining the budding virions at the cell surface. In addition, viral tethering by BST2 triggers NF-κB signaling to activate the innate immune responses against infections [50,51]. To evade this host antiviral response, an assortment of viral proteins evolved to antagonize BST2 by hijacking cellular ubiquitin-proteosome or endosome-lysosome pathways for the degradation or mistrafficking of BST2.

The presence of two membrane anchors on BST2 allows it to function as a direct tether between enveloped viruses and host cells. BST2 consists of an N-terminal cytoplasmic tail, a transmembrane helix, a coiled-coil ectodomain, and a C-terminal glycosylphosphatidylinositol (GPI) membrane anchor (Figure 4A). The coiled-coil ectodomain forms a long parallel dimer, which is stabilized by intermolecular disulfide bonds [52-55]. Protease and epitope mapping experiments suggest that the “axial” orientation, with the coiled-coil ectodomain perpendicular to the membranes, is likely the dominant configuration of functional BST2 (Figure 2B) [56•]. However, the results do not rule out the possibility that the tetrameric form of BST2, observed in the crystal structures [53-55], also contributes to virion tethering (Figure 2B). Interestingly, the C-terminus of BST2 was found incorporated in the virion more often than the N-terminus.

Figure 4. Mechanism of virion trapping by BST2 and its antagonization by HIV-1 Vpu-mediated mistrafficking.

Figure 4

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(A) Domain organization of BST2. (B) Models for possible configurations of BST2 in trapping of HIV virions, based on the crystal structure of the BST2 ectodomain (PDB ID: 3MQ7). BST2 is in cylinder and ribbon representation with the GPI anchors shown as red insertions into the membranes. (C) Model of Vpu-mediated mistrafficking of BST2, based on the crystal structure of BST2 and Vpu cytoplasmic domains in complex with the clathrin AP1 core (PDB ID: 4P6Z). The overall binding is achieved by a combination of binary associations between each pair of components (Vpu, AP1, and BST2). (D) Binding of the ExxxLV motif of Vpu (cyan ribbon and sticks) to the acidic dileucine motif-binding pocket in AP1 (yellow and pink surface). (E) Binding of BST2 cytoplasmic domain (magenta ribbon and sticks) to the tyrosine motif-binding pockect of AP1 (green surface) via the YxYxxV motif in BST2.

Retaining the N-terminus of BST2 in the cytoplasm may be advantageous for the host, as determinants in the N-terminal tail control the internalization and trafficking of trapped virions for lysosomal degradation. The BST2-mediated activation of NF-κb-associated immune responses also depends on the BST2 N-terminal tail.

BST2 is antagonized by HIV-1 Vpu and diverse viral proteins from other viruses [57]. In fact, prior to the discovery of its anti-HIV activity, BST2 was found to be counteracted by the K5 protein from the Karposi sarcoma-associated herpesvirus (KSHV) [58]. The great variety of BST2-antogonizing strategies highlights the convergent evolution of viruses for targeting this broad-spectrum antiviral factor.

HIV-1 Vpu utilizes two possible methods to decrease BST2 at the cell surface: i) the β-TrCP-dependent ubiquitination and lysosomal degradation of BST2 and ii) the mistrafficking of BST2 in the clathrin-dependent membrane trafficking pathways. While the effects of the β-TrCP-associated pathways remain under debate, our understanding of the Vpu-mediated BST2 mistrafficking was greatly advanced by the crystal structure of a protein complex containing Vpu and BST2 cytoplasmic domains and the core of the clathrin adaptor protein complex 1 (AP1) (Figure 4C) [59••]. Vpu mimics a membrane cargo to associate with AP1 at its acidic dileucine cargo-binding site (Figure 4D), while simultaneously forming a tight transmembrane interaction with BST2. This ternary association substantially increases the weak binary binding between BST2 and AP1, causing mistrafficking. Furthermore, this structure provided insight into how endogenous BST2 traffics within the endosomal system via the clathrin dependent pathways. BST2 binds to the tyrosine motif-binding site of AP1 via a unique di-tyrosine motif (Figure 4E). In the absence of Vpu, such an interaction may facilitate the endocytosis of BST2-trapped virions for eventual degradation in the lysosome. Further work is needed to structurally address how the transmembrane helices of Vpu and BST2 interact and how other viruses antagonize BST2.

Concluding Remarks

Structural studies of the HIV restriction factors have brought unparalleled insight into HIV biology and the innate immunity of the host. Information gained regarding viral evasion of the host restriction is particularly valuable as it offers new opportunities for antiviral drug discovery. In addition, as the factors pose significant barriers for cross-species transmission of viruses, they may impede the use of animal models to study HIV. Thus, understanding the antiviral mechanisms of host restriction factors will improve the study of HIV infection in animal models. Even after the many recent advances discussed above, much research is still required to fully understand the mechanisms of action of the anti-HIV factors currently known, and more host restriction factors that are likely to be discovered in the future. Structural biology is expected to continue to provide major insights into the mechanisms of these complex host-viral interactions.

Highlights.

  • Trim5α senses HIV capsid patterns and achieves strong binding by avidity

  • MxB binds to the HIV capsid assembly and may interfere with HIV nuclear import

  • HIV-1 Vif hijacks a host E3 ubiquitin ligase to antagonize APOBEC3 proteins

  • Allosteric GTP and dNTPs together activate the tetrameric SAMHD1 dNTPase

  • HIV-1 Vpu hijacks clathrin AP1 for the mistrafficking of BST2/tetherin

Acknowledgements

We would like to thank Jennifer Fribourgh, Henry Nguyen, Xiaoyun Ji, Chenxiang Tang, Brady Summers, Olga Buzovetsky, and Wei Wang for stimulating discussions and editorial contributions. This work was supported by the NIH grants (AI102778 and AI097064).

Footnotes

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