APOBEC3 in Viral Immunity Spyridon Stavrou and Susan R. Ross J Immunol 2015; 195:4565-4570; ; This information is current as doi: 10.4049/jimmunol.1501504 of September 28, 2021. http://www.jimmunol.org/content/195/10/4565 Downloaded from References This article cites 108 articles, 49 of which you can access for free at: http://www.jimmunol.org/content/195/10/4565.full#ref-list-1

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APOBEC3 Proteins in Viral Immunity Spyridon Stavrou and Susan R. Ross Apolipoprotein B editing complex 3 family members APOBEC3 proteins inhibit replication of HIV-1 lacking are cytidine deaminases that play important roles in vif, which encodes a 23-kDa (1, 20–23). In - intrinsic responses to infection by and producer cells, Vif binds APOBEC3D, APOBEC3F, have been implicated in the control of other , APOBEC3G, and APOBEC3H, targeting them for ubiq- such as parvoviruses, herpesviruses, papillomaviruses, uitinylation and degradation in the proteasome through hepatitis B virus, and . Although interactions with a number of cellular factors, including their direct effect on modification of viral DNA has CBF-b, Cul5, and elongins. This prevents APOBEC3 been clearly demonstrated, whether they play addi- packaging and, thereby, overcomes the antiviral activity (24–30). In contrast, in producer cells infected with vif- tional roles in innate and adaptive immunity to viruses Downloaded from is less clear. We review the data regarding the various deficient HIV or with retroviruses that do not express a Vif steps in the innate and adaptive immune response to protein, APOBEC3 proteins are packaged into virions via virus infection in which apolipoprotein B editing com- interaction with the nucleocapsid protein and viral RNA plex 3 proteins have been implicated. The Journal of (31–35). Immunology, 2015, 195: 4565–4570. Once packaged, APOBEC3 proteins inhibit infection by

deaminating residues on minus-strand DNA http://www.jimmunol.org/ produced by reverse , introducing G-to-A he genomes of and other species contain mutations in newly synthesized HIV-1 coding strand DNA. many that restrict infection by viruses. Many This leads to both degradation of reversed-transcribed DNA antiviral intrinsic restriction factors were discovered T prior to integration and to lethal G-to-A coding strand through the identification of viral products that counteract mutations in the integrated (36). APOBEC3G most their action. For example, apolipoprotein B editing complex often deaminates C residues in CC motifs, whereas the other (APOBEC)3G, a (CDA) belonging to the activation-induced CDA (AIDCDA)/APOBEC , APOBEC3 proteins preferentially modify those found in CT motifs (20, 37, 38). Because APOBEC3G-induced mutations was found because the HIV-1–encoded by guest on September 28, 2021 (Vif) blocks its activity (1). Many host antiviral genes, in- commonly occur in TGG motifs, often converts cluding those in the APOBEC3 family, have undergone positive the tryptophan codon TGG to a TAG stop codon; in con- selection by infectious pathogens, resulting in polymorphisms trast, the other human APOBEC3 proteins, as well as mouse in both regulatory and coding regions (2–5). In addition to the APOBEC3, generate GAA or GA to AAA and AA muta- sequence heterogeneity found in polymorphic alleles within tions, which more frequently result in missense mutations a given species, the number of APOBEC3 genes in different (22, 39, 40). APOBEC3-mediated sublethal mutagenesis could species varies as a result of expansion or contraction of the lead to both drug-resistant and immune-escape viruses, and locus, ranging from one gene in mice and rats to seven in lethal mutations may result in the production of truncated primates (APOBEC3A, APOBEC3B, APOBEC3C, APOBECDE, viral proteins degraded by the cell’s proteolytic processing APOBEC3F, APOBEC3G and APOBEC3H) (3, 5–10). Poly- pathways, thereby increasing Ag presentation (see “APOBEC3 morphisms in the mouse Apobec3 gene have been linked to and the adaptive immune response”) (41). susceptibility to infection by murine retroviruses (11–13), APOBEC3 proteins also inhibit virus replication by whereas at least one polymorphic APOBEC3H allele (HapII) CDA-independent mechanisms (42) (Fig. 1). For example, is believed to confer resistance to HIV-1 infection and disease APOBEC3F lacking CDA activity is as effective as the wild- progression; genome-wide association studies also implicated typeproteinininhibitingHIV-1infection,atleastincul- other human APOBEC3 polymorphisms in HIV-induced tured cells (43). In vitro studies suggested that APOBEC3 disease (11, 14–19). Because HIV is a relatively recent virus proteins inhibit elongation and accumulation of HIV-1, in humans, it is likely that other infectious agents contributed murine leukemia virus, and mouse mammary tumor virus to the positive selection of APOBEC3s. reverse-transcription products (44–46). APOBEC3 proteins

Department of Microbiology, Abramson Cancer Center, Institute for Immunology, Address correspondence and reprint requests to Dr. Susan R. Ross, Perelman School of Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104-6142 Medicine, University of Pennsylvania, 313 BRBII/III, 421 Curie Boulevard, Philadel- phia, PA 19104-6142. E-mail address: [email protected] ORCID: 0000-0002-3094-3769 (S.R.R.). Abbreviations used in this article: APOBEC, apolipoprotein B editing complex; CDA, Received for publication July 6, 2015. Accepted for publication August 24, 2015. cytidine deaminase; DC, dendritic cell; FV, Friend murine leukemia virus; ISG, IFN- This work was supported by Public Health Service Grant R01-AI-085015, National stimulated gene; STING, stimulator of IFN genes; Vif, viral infectivity factor. Institutes of Health Grants T32-CA115299 and F32-AI100512, and a Mathilde Krim Fellowship in Basic Biomedical Research (American Foundation for AIDS Research Copyright Ó 2015 by The American Association of Immunologists, Inc. 0022-1767/15/$25.00 108993-57-RKHF).

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1501504 4566 BRIEF REVIEWS: APOBEC3 AND VIRUSES also inhibit infection by parvoviruses, as well as retroelement packaged viruses in the case of these other virus families is not mobilization, without extensively hypermutating their genomes known. (47–51). Although virion-packaged proteins appear to restrict in- APOBEC3 expression in cells of the immune system fection of T cells, APOBEC3 proteins expressed in human The different APOBEC3 proteins are expressed at various and mouse myeloid and dendritic cells (DCs) also can restrict levels in hematopoietic cell populations, including CD4+ incoming HIV, mouse mammary tumor virus, and murine and CD8+ subsets (e.g., naive and memory), B cells, leukemia virus by both CDA-dependent and -independent and myeloid cells (55, 61, 62). CD4+ T cell expression of means (52–57). APOBEC3 proteins also were implicated in APOBEC3 proteins clearly plays a role in virus restriction. hypermutating and restricting the hepadnavirus hepatitis B Analysis of the deamination motifs found in HIV-1 cDNA virus and human papillomavirus in hepatocytes and kerati- isolated from CD4+ T cells indicates that APOBEC3G is the nocytes, respectively, as well as HSV-1 and EBV in estab- dominant antiviral protein in this cell type (63). Moreover, lished cell lines and primary patient samples (58–60); HIV-1 proviral DNA hypermutation combined with increased whether this is the result of target cell APOBEC3 activity or APOBEC3G expression levels was linked to lower virus repli- Downloaded from

A http://www.jimmunol.org/ UGG GAA A3G Other A3 ACC CTT

IFN

Paracrine IFN/cytokines UGG Exosome A3 ACC

D by guest on September 28, 2021 B B UUU

UNG2 BER C TAG DDR or NKG2D-L AAA

↑NKG2D-L TAG

or

Production of dead or AAA attenuated virus

NK cell

CD8 T cell FIGURE 1. Role of APOBEC3 proteins in antiviral immunity. APOBEC3 proteins are ISGs, whose expression is induced by IFNs and other chemokines/cytokines produced by cells in response to infection. APOBEC3 molecules are either packaged into virions or produced by the target cell, leading to deamination of residues in viral reverse-transcribed DNA; this leads to the generation of stop codons, in the case of A3G (red molecule) or missense mutations with the other A3 proteins (blue molecule). Certain cells, such as B cells, may also shed APOBEC3 in exosomes, which can be transmitted to virus-infected cells and either be packaged into viruses (A) or deaminate viral reverse transcripts that then integrate into the genome. These cells, as well as cells directly infected with virions containing packaged A3 (B), produce dead or attenuated viruses. When APCs are infected (C), the introduction of mutations generates truncated or misfolded proteins, which are degraded by the proteasome and provide MHC class I epitopes, leading to increased CTL responses and destruction of infected cells. In other cells (D), U residues in DNA generated by APOBEC3-mediated deamination are cleaved by UNG2, generating gaps that are acted upon by the cell’s base excision–repair (BER) machinery, triggering a DNA damage response (DDR). This, in turn, induces increased NK ligand expression and NK-mediated killing of infected cells. The Journal of Immunology 4567 cation and increased CD4+ T cells counts in patients (64–67), to be a major exosomal component, and exosomes bearing although individuals carrying the anti–HIV-1 APOBEC3H APOBEC3G can confer anti–HIV-1 activity to Jurkat T cells HapII allele also display lower levels of infection and higher (83). APOBEC3G levels are upregulated upon treatment of CD4+ T cells counts compared with individuals carrying B cells with a combination of agonists, such as CD40L, IL-4, other APOBEC3H alleles (14). More recent work suggests and anti–HLA class II Abs, and autologous CD4+ T cells that both cytidine deamination and reverse-transcription inhi- cocultured with B cells activated with these agonists are sig- bition play a role in HIV-1 restriction in primary CD4+ T cells nificantly less infected by HIV-1 (84). This suggests that (63). APOBEC3G derived from exosomes produced by activated are also major targets of infection by HIV and B cells confers antiviral activity to CD4+ T cells (84). B cell– other retroviruses, particularly at mucosal surfaces, serving not expressed APOBEC3 proteins may also act on other viruses only as latent reservoirs but also as APCs (68). However, that infect this cell type, such as EBV (58). macrophages are relatively resistant to infection due to the expression of APOBEC3 proteins, as well as additional APOBEC3 and the innate immune response cell host restriction factors, such as SAM domain and HD As discussed, APOBEC3 genes are IFN-stimulated genes domain-containing protein 1; the latter is believed to deplete (ISGs) whose expression is increased in response to various the dNTP pools available to for viral stimuli, including the ligands of TLR3, TLR4, and TLR7 (52, cDNA synthesis (69–72). Macrophages express APOBEC3G, 80, 81, 85–89). Thus, the activation of innate immune re- APOBEC3F, and APOBEC3DE, and their upregulation is sponses that occurs upon infection with many viruses could Downloaded from IFN-a dependent, although APOBEC3G restricts HIV-1 lead to increased APOBEC3 activity. This might be especially more potently than the combined effect of APOBEC3F and important for combating viruses acquired at mucosal sites of APOBEC3DE in this cell type (62, 73). Target cell expression infection, where sentinel cell targets, such as macrophages and in primary macrophages may also play a role in restricting DCs, are poised to mount such responses. HIV, as well as other retroviruses (45, 54, 55). APOBEC3A Expression of IFNs and other cytokines/chemokines is in- is also expressed at high levels in monocytes, whereas fully duced by virus infection, the result, in part, of cytosolic nucleic http://www.jimmunol.org/ differentiated macrophages express low levels (74); how- acid sensors that detect single- and double-stranded RNA ever, expression of APOBEC3A is strongly and DNA (reviewed in Ref. 90). Studies showed that reverse- enhanced by IFN-a treatment (55, 62, 74). This difference in transcribed retroviral DNA is recognized by several sensors, APOBEC3A levels between monocytes and macrophages cor- including cyclic GMP-AMP synthase and members of the relates with susceptibility to HIV-1 infection, with monocytes absent in melanoma 2 (AIM2)-like receptor family that being more resistant to infection than macrophages; when subsequently signal through the stimulator of IFN genes APOBEC3A was silenced in HIV-1–infected monocytes, virus (STING) pathway (91–93). As described above, APOBEC3 production was increased (69, 74). APOBEC3G induction by proteins inhibit reverse transcription in addition to intro- by guest on September 28, 2021 IFN-a in CD14+ monocytes is also significantly higher in ducing CDA-induced mutations. Thus, APOBEC3-mediated HIV-1–exposed but seronegative individuals than in HIV- inhibition of reverse transcription would seemingly limit cy- infected individuals or healthy controls (75). Only a small tosolic sensing and the IFN-induced antiviral response. In- percentage (#6%) of HIV-1 sequences from infected macro- deed, we showed recently that, in mice, APOBEC3 in phages contain G-to-A hypermutations; thus, it is possible that macrophages limits the levels of retroviral reverse transcripts APOBEC3 restriction of in macrophages occurs that trigger cytosolic sensing (93). However, reverse tran- primarily by CDA-independent means (55). scripts that escaped this blockade activated the STING Immature myeloid DCs can be productively infected by pathway via cytosolic sensing and induced type 1 IFN ex- HIV-1; these cells may also be used by HIV-1 as a “Trojan pression. This, in turn, increased expression of ISGs like horse” to allow for the transmission of virus to the lymph APOBEC3, reducing virus loads in vivo. Because human nodes, thus bringing it in the proximity of T cells (76, 77). APOBEC3 proteins also block reverse transcription in senti- Transmission of virus from DCs to T cells likely occurs by nel cells and reverse transcripts trigger STING via direct cell–cell transmission via immunological synapses (78, cytosolic sensing, it is likely that similar interactions between 79). However, myeloid DCs support only a limited amount the two restriction pathways occur during HIV infection. of HIV replication; this has been attributed, at least in part, to Interestingly, DNA viruses, like herpesviruses, also induce cell host restriction factors, such as APOBEC3 proteins. Ac- IFN production via the cytosolic sensor–STING pathway and tivation of myeloid DCs by IFN-a results in the potent up- would be predicted to induce antiviral APOBEC3 expression regulation of APOBEC3A, APOBEC3F, and APOBEC3G, that could then act on these viruses. This interplay between without the induction of signals that lead to their maturation innate immune sensors and APOBEC3 is likely to afford (74, 80, 81). Unlike macrophages, HIV-1 DNA in myeloid multiple layers of protection to host against infection by DCs is hypermutated upon IFN-a treatment; transmission multiple virus families. from myeloid DCs to T cells is significantly reduced com- APOBEC3G also was linked to increased destruction of pared with IFN-naive cells (80). HIV-1–infected cells by NK cells (94). Cells infected with HIV B cell expression of APOBEC3G is higher than that seen in lacking or encoding defective Vifs unable to bind APOBEC3G monocytes (62); nevertheless, because B cells lack the entry have higher levels of the NKG2D ligands, such as ULBPs and receptors required for HIV-1 infection, APOBEC3G is un- PLAP, resulting in more efficient NK cell–mediated lysis. The likely to play a role in cell-intrinsic restriction. However, increase in lysis was linked to higher content in HIV B cells are a major source of exosome production upon reverse transcripts caused by APOBEC3G-mediated cytidine CD40L and IL-4 stimulation (82). APOBEC3G was shown deamination. are removed from DNA via cleavage by 4568 BRIEF REVIEWS: APOBEC3 AND VIRUSES uracil–DNA glycosylase, which then activates the base excision– response is likely due to APOBEC3-mediated suppression of repair pathway. This, in turn, generates gaps or breaks in DNA virus infection at early times, thereby limiting the number of and subsequently induces the DNA-damage response, a known virus-producing cells in the early stages of infection. This may inducer of NKG2D ligand expression (94) (Fig. 1). Thus, reduce Ag load and the induction of immune tolerance or another antiviral function of APOBEC3G may be to recruit prevent FV-mediated damage of critical hematopoietic lineage lymphocyte effectors, such as NK cells, which, in turn, cells required for generating an immune response (102, 103). eliminate infected cells. Whether other human APOBEC3 APOBEC3 may also play a role in somatic hypermutation of proteins also affect NK recognition of HIV or other virus- Abs. AID is the primary CDA involved in somatic hypermutation infected cells remains to be determined. of Ig genes that results in the diverse repertoire of Abs needed to clear infections (104). One study found that IgH sequences of APOBEC3 and the adaptive immune response FV-specific mAbs derived from APOBEC3-knockout mice had Clearly, APOBEC3 proteins play a role in the intrinsic/innate significantly lower levels of C-to-T and G-to-A somatic hyper- response to, and the subsequent control of, early virus infec- mutation and lower virus-binding ability than did those from tion. There is increasing evidence that APOBEC3 proteins also wild-type mice (105). However, it is not clear that Ig somatic contribute to the adaptive immune response by affecting the mutations are critical for the control of FV, because AID- generation of CTLs that recognize viral peptides and perhaps knockout mice produce virus-neutralizing IgM Abs and control B cell production of antiviral Abs. Because APOBEC3 ex- infection (106). Nevertheless, because the human APOBEC3 pression is induced by virus infection of APCs, as discussed proteins APOBEC3A and APOBEC3B have been implicated in Downloaded from above, this may afford additional layers of host protection. mutating genomic DNA, it is possible that they contribute to the It is well-known that viruses causing persistent infection, like development of neutralizing Abs during virus infection (107, 108). HIV-1, generate escape variants. HIV may take advantage of Conclusions nonlethal mutations induced by APOBEC3 proteins to gen- erate such CTL escape variants (95); APOBEC3G/F hotspots Organisms adapt to infectious agents by developing protective in the HIV genome are enriched in immunogenic CTL epi- responses; conversely, infectious agents develop adaptive coun- http://www.jimmunol.org/ topes, and deamination at these hotspots diminished CD8+ termeasures to these responses. Host defenses against infectious T cell responses to infected cells (39, 40). Thus, it may be agents include various mechanisms of innate immunity (e.g., beneficial for the virus to preserve APOBEC3G mutation NK cells, TLRs, and IFNs) and adaptive immunity (humoral hotspots at locations that influence the presentation and rec- and cell mediated). APOBEC3 proteins have clear roles in ognition of T cell epitopes and thereby aid in immune escape. conferring intrinsic host resistance to infection to different In contrast, the host may strengthen its intrinsic ability to viruses as a result of their ability to directly act on viral control HIV-1 infection by selecting for immune escape genomes, thereby generating mutations or blocking viral nucleic acid synthesis. There is also a body of evidence, par- variants; there are known CD8 epitopes in Vif itself and Vif by guest on September 28, 2021 immune escape variants would be predicted to more weakly ticularly in the case of retroviruses, that APOBEC3 deaminase counteract APOBEC3s (96, 97). activity plays additional antiviral roles in innate and adaptive CTL responses to viruses may also be increased through immunity. Whether these additional mechanisms operate in APOBEC3G-generated stop codons, leading to premature the antiviral response to other virus families remains to be truncation of proteins and degradation via Ag-processing determined. Moreover, it will be important to demonstrate pathways in HIV-1–infected cells (98, 99) (Fig. 1). Indeed, that these additional roles for APOBEC3 proteins function in the virus-specific CTL response to APOBEC3G-expressing, the context of virus infection in vivo. HIV-infected APCs is increased compared with APCs that do not express the CDA (99). Moreover, the activation of HIV- Disclosures specific CTLs was stronger with vif-deficient HIV-infected The authors have no financial conflicts of interest. APCs. However, a recent report that longitudinally followed pol and env sequences in a large cohort of patients chron- References ically infected with HIV-1 found that the vast majority of 1. Sheehy, A. M., N. C. Gaddis, J. D. Choi, and M. H. Malim. 2002. Isolation of the G-to-A mutations fell into the recognition motif for a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature 418: 646–650. APOBEC3F and the other APOBEC3 proteins and not 2. Sobieszczyk, M. E., J. R. Lingappa, and M. J. McElrath. 2011. Host genetic that of APOBEC3G (39). In this case, missense mutations polymorphisms associated with innate immune factors and HIV-1. Curr. Opin. HIV AIDS 6: 427–434. in viral proteins could also lead to misfolding and protein 3. Ross, S. R. 2009. 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