Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

Trapp, Susanna; Derby, Nina; Singer, Rachel; Shaw, Andrew; Williams, Vennansha G.; Turville, Stuart; Bess, Julian W.; Lifson, Jeffrey D.; Robbiani, Melissa

doi:10.1128/jvi.00023-08

Cited by 69 publications

(92 citation statements)

References 78 publications

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“…S6) by flow cytometry and found that groups 3 and 5 had higher A3G + cell percentages mostly in monocytes and DCs and only a small proportion (less than onethird) in the CD4 + T-cell compartment. In contrast to T cells (32), monocytes and DCs express primarily the protective low molecular mass (LMM) form of A3G (20,33,34). Significant inverse correlations were observed between the A3G expression increase and the set-point plasma (Fig.…”

Section: Resultsmentioning

confidence: 84%

“…In addition, mucosal immunization led to persistent expression of A3G in macaques (19). PolyI:C, one component of our vaccine adjuvant, was reported to inhibit HIV amplification in DCs via A3G induction (20). In the current macaque study, we demonstrated an innate mechanism by which adjuvants may contribute to viral control, and identified candidate adaptive immune correlates of protection.…”

mentioning

confidence: 75%

“…We identified that the enhanced A3G expression was widely distributed in DCs, monocyte/macrophage, and CD4 + T cells. It worth mention that APCs, such as DCs and CD14 + monocytes, which express mainly the protective LMM form of A3G (20,33,34), were the main A3G + cells in MLN and colon IEL (Fig.3 D and E). DCs play a critical role in mediating HIV transmission in the mucosal tissues.…”

Section: Discussionmentioning

confidence: 99%

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Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Sui

Zhu

Gagnon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

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Adjuvant effects on innate as well as adaptive immunity may be critical for inducing protection against mucosal HIV and simian immunodeficiency virus (SIV) exposure. We therefore studied effects of Toll-like receptor agonists and IL-15 as mucosal adjuvants on both innate and adaptive immunity in a peptide/poxvirus HIV/SIV mucosal vaccine in macaques, and made three critical observations regarding both innate and adaptive correlates of protection: (i) adjuvant-alone without vaccine antigen impacted the intrarectal SIVmac251 challenge outcome, correlating with surprisingly long-lived APOBEC3G (A3G)-mediated innate immunity; in addition, even among animals receiving vaccine with adjuvants, viral load correlated inversely with A3G levels; (ii) a surprising threshold-like effect existed for vaccine-induced adaptive immunity control of viral load, and only antigen-specific polyfunctional CD8 + T cells correlated with protection, not tetramer + T cells, demonstrating the importance of T-cell quality; (iii) synergy was observed between Toll-like receptor agonists and IL-15 for driving adaptive responses through the up-regulation of IL-15Rα, which can present IL-15 in trans, as well as for driving the innate A3G response. Thus, strategic use of molecular adjuvants can provide better mucosal protection through induction of both innate and adaptive immunity.

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Section: Resultsmentioning

confidence: 84%

mentioning

confidence: 75%

Section: Discussionmentioning

confidence: 99%

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Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Sui

Zhu

Gagnon

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

110

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“…However, two studies in primary cells are at odds with findings in 293T cells. One reported that A3A inhibits HIV-1 replication in monocytes (51), whereas the other reported that A3A expression correlates with inhibition of HIV-1 replication in dendritic cells (53). Neither study addressed the mechanism by which A3A could inhibit HIV-1 replication in these primary cell types, given that A3A is not properly packaged into the HIV-1 core.…”

Section: Discussionmentioning

confidence: 91%

“…Others have noted that use of this antiserum results in detection of two ϳ20-kDa A3 proteins in dendritic cells and monocytes (47,53). Although these proteins were initially described as possible A3G degradation products (53), a subsequent publication (47) noted that they are likely to represent APOBEC3A (A3A), an A3 protein that contains only a single deaminase domain and shares 27 of its 29 C-terminal amino acids with A3G.…”

Section: Tc-but Not Cc-specific Deaminase Activity Is Induced In Pbmcmentioning

confidence: 99%

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Thielen

McNevin

McElrath

et al. 2010

Journal of Biological Chemistry

105

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In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date. In contrast, here we report high levels of deaminase activity at TC motifs when whole PBMCs or isolated primary monocyte-derived cells were treated with interferon-␣ (IFN␣) or IFN␣-inducing toll-like receptor ligands. Induction of TC-specific deaminase activity required new transcription and translation and correlated with the appearance of two APOBEC3A (A3A) isoforms. Knockdown of A3A in monocytes with siRNA abolished TC-specific deaminase activity, confirming that A3A isoforms are responsible for all TC-specific deaminase activity observed. Both A3A isoforms appear to be enzymatically active; moreover, our mutational studies raise the possibility that the smaller isoform results from internal translational initiation. In contrast to the high levels of TC-specific activity observed in IFN␣-treated monocytes, CC-specific activity remained low in PBMCs, suggesting that A3G deaminase activity is relatively inhibited, unlike that of A3A. Together, these findings suggest that deaminase activity of A3A isoforms in monocytes and macrophages may play an important role in host defense against viruses. A33 proteins are cytidine deaminases that are capable of inhibiting replication of retroviruses, DNA viruses, and retroelements (reviewed in Refs. 1-3). The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined). Although APOBEC3G (A3G), the best understood A3 protein, acts preferentially on CC motifs, the six other human A3 proteins display varying degrees of preference for TC motifs (4 -13). Because other cytidine deaminases, such as activation-induced deaminase and APOBEC1, either display a strong preference for editing deoxycytidines in other dinucleotide contexts or act on TC motifs in RNA (4), mutations that arise in a CC or TC context in DNA constitute signatures of editing by A3 proteins.Much headway has been made in understanding how A3 proteins act on HIV-1 DNA, in part through transfection of A3 plasmids into human epithelium-derived cell lines, such as 293T or HeLa cells, which lack significant endogenous expression of most A3 proteins. From such studies, A3G and APOBEC3F (A3F) are known to be packaged into virus particles when the HIV-1 Vif protein is not expressed and to cause a substantial reduction in virus infectivity (5, 12, 14 -16). Reduced virus infectivity results in part from non-enzymatic inhibition of reverse transcription by A3G and A3F (17-2...

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Triggering of TLR‐3, ‐4, NOD2, and DC‐SIGN reduces viral replication and increases T‐cell activation capacity of HIV‐infected human dendritic cells

et al. 2017

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A variety of signals influence the capacity of dendritic cells (DCs) to mount potent antiviral cytotoxic T-cell (CTL) responses. In particular, innate immune sensing by pathogen recognition receptors, such as TLR and C-type lectines, influences DC biology and affects their susceptibility to HIV infection. Yet, whether the combined effects of PPRs triggering and HIV infection influence HIV-specific (HS) CTL responses remain enigmatic. Here, we dissect the impact of innate immune sensing by pathogen recognition receptors on DC maturation, HIV infection, and on the quality of HS CTL activation. Remarkably, ligand-driven triggering of TLR-3, -4, NOD2, and DC-SIGN, despite reducing viral replication, markedly increased the capacity of infected DCs to stimulate HS CTLs. This was exemplified by the diversity and the quantity of cytokines produced by HS CTLs primed by these DCs. Infecting DCs with viruses harboring members of the APOBEC family of antiviral factors enhanced the antigen-presenting skills of infected DCs. Our results highlight the tight interplay between innate and adaptive immunity and may help develop innovative immunotherapies against viral infections.

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Double-Stranded RNA Analog Poly(I:C) Inhibits Human Immunodeficiency Virus Amplification in Dendritic Cells via Type I Interferon-Mediated Activation of APOBEC3G

Abstract: Human immunodeficiency virus (HIV) is taken up by and replicates in immature dendritic cells (imDCs),

Cited by 69 publications

References 78 publications

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Innate and adaptive immune correlates of vaccine and adjuvant-induced control of mucosal transmission of SIV in macaques

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Triggering of TLR‐3, ‐4, NOD2, and DC‐SIGN reduces viral replication and increases T‐cell activation capacity of HIV‐infected human dendritic cells

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