Innate Immune Sensing of HIV-1 by Dendritic Cells
2012; Cell Press; Volume: 12; Issue: 4 Linguagem: Inglês
10.1016/j.chom.2012.10.002
ISSN1934-6069
Autores Tópico(s)Immunotherapy and Immune Responses
ResumoHIV-1-specific antibodies and CD8+ cytotoxic T cells are detected in most HIV-1-infected people, yet HIV-1 infection is not eradicated. Contributing to the failure to mount a sterilizing immune response may be the inability of antigen-presenting dendritic cells (DCs) to sense HIV-1 during acute infection, and thus the inability to effectively prime naive, HIV-1-specific T cells. Recent findings related to DC-expressed innate immune factors including SAMHD1, TREX1, and TRIM5 provide a molecular basis for understanding why DCs fail to adequately sense invasion by this deadly pathogen and suggest experimental approaches to improve T cell priming to HIV-1 in prophylactic vaccination protocols. HIV-1-specific antibodies and CD8+ cytotoxic T cells are detected in most HIV-1-infected people, yet HIV-1 infection is not eradicated. Contributing to the failure to mount a sterilizing immune response may be the inability of antigen-presenting dendritic cells (DCs) to sense HIV-1 during acute infection, and thus the inability to effectively prime naive, HIV-1-specific T cells. Recent findings related to DC-expressed innate immune factors including SAMHD1, TREX1, and TRIM5 provide a molecular basis for understanding why DCs fail to adequately sense invasion by this deadly pathogen and suggest experimental approaches to improve T cell priming to HIV-1 in prophylactic vaccination protocols. Currently, more than 30 drug formulations are approved that block HIV-1 replication and prevent infected individuals from progressing to AIDS (http://www.fda.gov). However, treatment with these drugs is lifelong and plagued with toxicity, virus-drug resistance, and significant economic cost. According to recent figures from UNAIDS, 34 million people are infected with HIV-1, and for each person who starts anti-HIV-1 drug treatment, it is estimated that there are 2–3 new infections. In 2010, 1.8 million people died of AIDS-related illnesses and 2.6 million became infected with HIV-1. Efforts to control the AIDS pandemic would benefit from an effective anti-HIV-1 vaccine, but with perhaps one exception (Rerks-Ngarm et al., 2009Rerks-Ngarm S. Pitisuttithum P. Nitayaphan S. Kaewkungwal J. Chiu J. Paris R. Premsri N. Namwat C. de Souza M. Adams E. et al.MOPH-TAVEG InvestigatorsVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.N. Engl. J. Med. 2009; 361: 2209-2220Crossref PubMed Scopus (903) Google Scholar), attempts to prevent new HIV-1 infection in human vaccine trials have been unsuccessful. The eradication of smallpox and the effective control of poliovirus, measles, mumps, rubella, and yellow fever offer stark contrast to the public health experience with HIV-1. The live virus preparations used to immunize against these pathogens were developed empirically, without understanding the mechanisms that underlie the anamnestic response. The success of the vaccines against these viruses—particularly those vaccines that replicate within the host—demonstrates that lifelong protective immune responses can be elicited by vaccination. In contradistinction, people infected with HIV-1 progress to AIDS despite measurable humoral and cellular immune responses to HIV-1 (Virgin and Walker, 2010Virgin H.W. Walker B.D. Immunology and the elusive AIDS vaccine.Nature. 2010; 464: 224-231Crossref PubMed Scopus (87) Google Scholar). Worse still, HIV-1-infected people with documented, broad anti-HIV-1 immune responses can be secondarily infected with HIV-1 (Altfeld et al., 2002Altfeld M. Allen T.M. Yu X.G. Johnston M.N. Agrawal D. Korber B.T. Montefiori D.C. O'Connor D.H. Davis B.T. Lee P.K. et al.HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus.Nature. 2002; 420: 434-439Crossref PubMed Scopus (234) Google Scholar; Smith et al., 2005Smith D.M. Richman D.D. Little S.J. HIV superinfection.J. Infect. Dis. 2005; 192: 438-444Crossref PubMed Scopus (95) Google Scholar). Interestingly, failure to protect against reinfection is also seen with Hepatitis C virus (Blackard and Sherman, 2007Blackard J.T. Sherman K.E. Hepatitis C virus coinfection and superinfection.J. Infect. Dis. 2007; 195: 519-524Crossref PubMed Scopus (25) Google Scholar), and no vaccine is available for this virus either. These observations do not mean that an HIV-1 prophylactic vaccine is impossible, especially given that superinfection with HIV-1 might be aided by the immune dysfunction associated with prior HIV-1 infection. Nonetheless, these observations demonstrate that the immune response targeting HIV-1 differs fundamentally from that against the viruses described above and suggest that, in the absence of some fundamental modification in vaccine design, even a live vaccine would be unlikely to alter the outcome of an HIV-1 challenge. While failure to elicit protective immunity distinguishes HIV-1 (and HCV) from pathogenic viruses such as poliovirus and measles, these are not the only viruses that have eluded efforts to develop a protective vaccine. Dengue infects 500 million people each year, two million of whom suffer complications of hemorrhagic fever (Beatty et al., 2010Beatty M.E. Stone A. Fitzsimons D.W. Hanna J.N. Lam S.K. Vong S. Guzman M.G. Mendez-Galvan J.F. Halstead S.B. Letson G.W. et al.Asia-Pacific and Americas Dengue Prevention Boards Surveillance Working GroupBest practices in dengue surveillance: a report from the Asia-Pacific and Americas Dengue Prevention Boards.PLoS Negl. Trop. Dis. 2010; 4: e890Crossref PubMed Scopus (39) Google Scholar). Like HIV-1, there are multiple types of Dengue virus, there is no good animal model, and there are no simple correlates of immunologic protection. The first protective Dengue vaccine—albeit with 30% efficacy—was possible only recently, after 50 years of research (Sabchareon et al., 2012Sabchareon A. Wallace D. Sirivichayakul C. Limkittikul K. Chanthavanich P. Suvannadabba S. Jiwariyavej V. Dulyachai W. Pengsaa K. Wartel T.A. et al.Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial.Lancet. 2012; (in press. Published online September 10, 2012)https://doi.org/10.1016/S0140-6736(12)61428-7Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar). These results are remarkably similar to the reported 31% efficacy in RV144, the only successful HIV-1 prophylactic vaccine trial (Rerks-Ngarm et al., 2009Rerks-Ngarm S. Pitisuttithum P. Nitayaphan S. Kaewkungwal J. Chiu J. Paris R. Premsri N. Namwat C. de Souza M. Adams E. et al.MOPH-TAVEG InvestigatorsVaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand.N. Engl. J. Med. 2009; 361: 2209-2220Crossref PubMed Scopus (903) Google Scholar). Respiratory Syncytial Virus (RSV) causes >100,000 hospitalizations for pneumonia each year in the United States (Welliver, 2003Welliver R.C. Review of epidemiology and clinical risk factors for severe respiratory syncytial virus (RSV) infection.J. Pediatr. 2003; 143: S112-S117Abstract Full Text Full Text PDF PubMed Google Scholar). As with HIV-1, RSV-specific immune responses are detectable after infection, but protection against recurrent infection is not conferred. Attempts to vaccinate against RSV even caused a paradoxical increase in disease severity, perhaps because the particular adjuvant used—alum—elicited a nonprotective CD4+ TH2 response (Lindell et al., 2011Lindell D.M. Morris S.B. White M.P. Kallal L.E. Lundy P.K. Hamouda T. Baker Jr., J.R. Lukacs N.W. A novel inactivated intranasal respiratory syncytial virus vaccine promotes viral clearance without Th2 associated vaccine-enhanced disease.PLoS ONE. 2011; 6: e21823Crossref PubMed Scopus (11) Google Scholar). Ultimately, any advance in mechanistic understanding of protective immunity targeting HIV-1 would likely benefit attempts to control Dengue virus, RSV, and other viruses as well. This review will assess the large body of literature on HIV-1 and construct a model to explain why the human immune system fails to eliminate or prevent HIV-1 infection. In large part, it will focus on recent developments regarding host cell restriction factors and attempt to link these findings to what is known about innate immune detection of HIV-1, T cell priming by DCs, and HIV-1 vaccine development. Several hypotheses offer plausible explanations for HIV-1 persistence in the face of apparent antiviral immunity. Soon after establishment of infection by one or a few HIV-1 virions, variants are selected in response to pressure from HIV-1-specific cytotoxic T lymphocytes (CTLs) and neutralizing antibody (Kearney et al., 2009Kearney M. Maldarelli F. Shao W. Margolick J.B. Daar E.S. Mellors J.W. Rao V. Coffin J.M. Palmer S. Human immunodeficiency virus type 1 population genetics and adaptation in newly infected individuals.J. Virol. 2009; 83: 2715-2727Crossref PubMed Scopus (65) Google Scholar; Henn et al., 2012Henn M.R. Boutwell C.L. Charlebois P. Lennon N.J. Power K.A. Macalalad A.R. Berlin A.M. Malboeuf C.M. Ryan E.M. Gnerre S. et al.Whole genome deep sequencing of HIV-1 reveals the impact of early minor variants upon immune recognition during acute infection.PLoS Pathog. 2012; 8: e1002529Crossref PubMed Scopus (45) Google Scholar). It should be noted that high mutagenic rates and complex mixtures of sequence variants known as quasi-species are also well described for other RNA viruses, including some viruses for which there are effective vaccines. The pathogenesis of poliovirus, for example, requires an error-prone viral polymerase and the quasi-species that it generates (Vignuzzi et al., 2006Vignuzzi M. Stone J.K. Arnold J.J. Cameron C.E. Andino R. Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population.Nature. 2006; 439: 344-348Crossref PubMed Scopus (295) Google Scholar). This suggests that it is not quasi-species per se that distinguishes HIV-1 from other viruses, but rather HIV-1's capacity to replicate in the face of enormous sequence variation. The HIV-1 Env glycoprotein, in particular, is distinguished by great sequence diversity and conformational flexibility, as well as an extensive glycan shield and viral entry receptor binding sites that are well concealed and only accessible to antibodies that have undergone extensive somatic mutation (Zhou et al., 2007Zhou T. Xu L. Dey B. Hessell A.J. Van Ryk D. Xiang S.-H. Yang X. Zhang M.-Y. Zwick M.B. Arthos J. et al.Structural definition of a conserved neutralization epitope on HIV-1 gp120.Nature. 2007; 445: 732-737Crossref PubMed Scopus (433) Google Scholar; Scheid et al., 2009Scheid J.F. Mouquet H. Feldhahn N. Seaman M.S. Velinzon K. Pietzsch J. Ott R.G. Anthony R.M. Zebroski H. Hurley A. et al.Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals.Nature. 2009; 458: 636-640Crossref PubMed Scopus (281) Google Scholar; Bar et al., 2012Bar K.J. Tsao C.-Y. Iyer S.S. Decker J.M. Yang Y. Bonsignori M. Chen X. Hwang K.-K. Montefiori D.C. Liao H.-X. et al.Early low-titer neutralizing antibodies impede HIV-1 replication and select for virus escape.PLoS Pathog. 2012; 8: e1002721Crossref PubMed Scopus (23) Google Scholar). Details about this extraordinary molecule and how broadly neutralizing antibodies might be generated by prophylactic vaccination is discussed in an accompanying review by Dennis Burton and colleagues (Burton et al., 2012Burton D.R. Ahmed R. Barouch D.H. Butera S.T. Crotty S. Godzik A. Kaufmann D.E. McElrath M.J. Nussenzweig M.C. Pulendran B. et al.A Blueprint for HIV Vaccine Discovery.Cell Host Microbe. 2012; 12 (this issue): 396-407Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar). Another intuitive explanation for the inability of the immune system to clear infection is that HIV-1 inactivates the same cells of the immune system that protect against viral infection. But tropism for immune cells, as well as the immunosuppression that results, is shared with viruses such as the measles virus, for which an effective vaccine exists (Tatsuo et al., 2000Tatsuo H. Ono N. Tanaka K. Yanagi Y. SLAM (CDw150) is a cellular receptor for measles virus.Nature. 2000; 406: 893-897Crossref PubMed Scopus (504) Google Scholar). Perhaps what is critical for HIV-1 persistence is the exact subclass of immune cell targeted by HIV-1 (Chomont et al., 2009Chomont N. El-Far M. Ancuta P. Trautmann L. Procopio F.A. Yassine-Diab B. Boucher G. Boulassel M.-R. Ghattas G. Brenchley J.M. et al.HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation.Nat. Med. 2009; 15: 893-900Crossref PubMed Scopus (229) Google Scholar) or the selective targeting of HIV-1-specific CD4+ T cells (Douek et al., 2002Douek D.C. Brenchley J.M. Betts M.R. Ambrozak D.R. Hill B.J. Okamoto Y. Casazza J.P. Kuruppu J. Kunstman K. Wolinsky S. et al.HIV preferentially infects HIV-specific CD4+ T cells.Nature. 2002; 417: 95-98Crossref PubMed Scopus (705) Google Scholar). Importantly, like all retroviruses, HIV-1 integrates its genome into host cell chromosomal DNA, where the virus becomes a permanent genetic element in the infected cell and in all daughter cells. This enables it to establish a reservoir of HIV-1-infected cells that persist indefinitely, even in the face of an otherwise effective immune response. In contrast, measles virus cannot integrate, it cannot establish a latent reservoir of infection, and it cannot persist after the measles virus-specific immune response is established. Histone deacetylase (HDAC) inhibitors activate latent HIV-1 provirus transcription and have been touted as a means to purge the latent reservoir of HIV-1-infected cells (Archin et al., 2012Archin N.M. Liberty A.L. Kashuba A.D. Choudhary S.K. Kuruc J.D. Crooks A.M. Parker D.C. Anderson E.M. Kearney M.F. Strain M.C. et al.Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy.Nature. 2012; 487: 482-485Crossref PubMed Scopus (89) Google Scholar). The underlying idea is that, upon transcriptional activation of latent HIV-1 proviruses, HIV-1 proteins will be synthesized that would render these infected cells detectable by HIV-1-specific cytotoxic T cells. However, upon activation of transcription by the HDAC inhibitors, the HIV-1-infected cells were not killed by autologous, HIV-1-specific CTL unless the CTL were stimulated with cognate antigen prior to provirus reactivation (Shan et al., 2012Shan L. Deng K. Shroff N.S. Durand C.M. Rabi S.A. Yang H.-C. Zhang H. Margolick J.B. Blankson J.N. Siliciano R.F. Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.Immunity. 2012; 36: 491-501Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). These experiments demonstrate that the HIV-1-specific CTL responses in these individuals were somehow defective. Recent research on HIV-1 interaction with dendritic cells (DCs) suggests another hypothesis to explain HIV-1 persistence. DCs are highly heterogeneous, antigen-presenting cells that initiate acquired immune responses by priming naive, antigen-specific T cells (Steinman and Idoyaga, 2010Steinman R.M. Idoyaga J. Features of the dendritic cell lineage.Immunol. Rev. 2010; 234: 5-17Crossref PubMed Scopus (57) Google Scholar). The nature of the T cell response that ensues, whether tolerance or sterilizing antiviral immunity, is determined by the maturation status of the antigen-presenting DC and the array of signals that the DC provides to the naive, antigen-specific T cell (Figure 1). Among the molecules relevant to T cell priming that DCs elaborate in response to maturation are cell surface MHC Class II, CD80 and CD86, and cytokines such as IL-12 that promote TH1 responses and the cytotoxic T lymphocytes that clear virus-infected cells (Reis e Sousa, 2006Reis e Sousa C. Dendritic cells in a mature age.Nat. Rev. Immunol. 2006; 6: 476-483Crossref PubMed Scopus (393) Google Scholar; Altfeld et al., 2011Altfeld M. Fadda L. Frleta D. Bhardwaj N. DCs and NK cells: critical effectors in the immune response to HIV-1.Nat. Rev. Immunol. 2011; 11: 176-186Crossref PubMed Scopus (67) Google Scholar). DCs mature when pattern recognition receptors (PRRs) are stimulated by pathogen-associated molecular patterns (PAMPS) (Akira et al., 2006Akira S. Uematsu S. Takeuchi O. Pathogen recognition and innate immunity.Cell. 2006; 124: 783-801Abstract Full Text Full Text PDF PubMed Scopus (3440) Google Scholar). Viruses are obligate intracellular parasites, largely dependent upon host cell machinery for replication. They therefore do not generate completely foreign molecules like lipopolysaccharide that distinguish them from the host. Instead, PRRs alert cells to the presence of viruses by detecting more subtle features such as structured replication intermediates, modified nucleic acids, or viral replication complexes in cellular compartments where nucleic acids are not normally found. Viral nucleic acids can be detected via cell-extrinsic or cell-intrinsic mechanisms (Iwasaki and Medzhitov, 2010Iwasaki A. Medzhitov R. Regulation of adaptive immunity by the innate immune system.Science. 2010; 327: 291-295Crossref PubMed Scopus (454) Google Scholar). The former include TLR activation after phagocytosis of virus-infected, apoptotic cells. Such extrinsic PRRs are not expressed by all cell types but are generally restricted to antigen-presenting or phagocytic cells, such as dendritic cells. Cell intrinsic mechanisms detect viral nucleic acid within the infected cell, and the PRRs that detect these PAMPs are generally expressed on a broad range of cell types, including fibroblasts. RIG-I and MDA-5 are cell intrinsic cytosolic receptors that detect structural features unique to viral RNA. A cell-intrinsic mechanism also exists for detecting viral DNA in the host cell cytoplasm. Cytosolic sensors for DNA include IFI16, DDX41, DAI, LSm14A, and AIM2 (Unterholzner et al., 2010Unterholzner L. Keating S.E. Baran M. Horan K.A. Jensen S.B. Sharma S. Sirois C.M. Jin T. Latz E. Xiao T.S. et al.IFI16 is an innate immune sensor for intracellular DNA.Nat. Immunol. 2010; 11: 997-1004Crossref PubMed Scopus (247) Google Scholar; Sharma and Fitzgerald, 2011Sharma S. Fitzgerald K.A. Innate immune sensing of DNA.PLoS Pathog. 2011; 7: e1001310Crossref PubMed Scopus (21) Google Scholar; Sharma et al., 2011Sharma S. DeOliveira R.B. Kalantari P. Parroche P. Goutagny N. Jiang Z. Chan J. 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DAI/ZBP1/DLM-1 complexes with RIP3 to mediate virus-induced programmed necrosis that is targeted by murine cytomegalovirus vIRA.Cell Host Microbe. 2012; 11: 290-297Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar). Optimal priming of naive T cells to generate potent CD4+ TH1 and CD8+ cytotoxic T cell responses requires that PAMP recognition by PRRs occur within the same DCs that present the antigen, at least under particular experimental conditions (Spörri and Reis e Sousa, 2005Spörri R. Reis e Sousa C. Inflammatory mediators are insufficient for full dendritic cell activation and promote expansion of CD4+ T cell populations lacking helper function.Nat. Immunol. 2005; 6: 163-170Crossref PubMed Scopus (278) Google Scholar; Hou et al., 2008Hou B. Reizis B. DeFranco A.L. 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Coexpression of PD-1 with another negative regulator of T cell activation, CD160, distinguishes a subset of ineffective HIV-1-specific CD8+ T cells from activated T cells (Peretz et al., 2012Peretz Y. He Z. Shi Y. Yassine-Diab B. Goulet J.-P. Bordi R. Filali-Mouhim A. Loubert J.-B. El-Far M. Dupuy F.P. et al.CD160 and PD-1 Co-Expression on HIV-Specific CD8 T Cells Defines a Subset with Advanced Dysfunction.PLoS Pathog. 2012; 8: e1002840Crossref PubMed Scopus (11) Google Scholar). While these ineffective, HIV-1-specific, CD8+ T cells are thought to reflect a state of immune exhaustion that arises during chronic infection with HIV-1 (Khaitan and Unutmaz, 2011Khaitan A. Unutmaz D. Revisiting immune exhaustion during HIV infection.Curr. HIV/AIDS Rep. 2011; 8: 4-11Crossref PubMed Scopus (30) Google Scholar), similar phenotypes are observed in short-term experiments ex vivo and in humanized mice (Brainard et al., 2009Brainard D.M. Seung E. Frahm N. Cariappa A. Bailey C.C. Hart W.K. 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Immunol. 2010; 40: 2248-2258Crossref PubMed Scopus (19) Google Scholar), suggesting that T cell priming to HIV-1 antigens in the absence of optimal DC maturation might contribute to these ineffective, anti-HIV-1 immune responses. Innate immune detection of viral nucleic acid generally activates type 1 interferon (IFN) and a large number of IFN-stimulated genes with a range of antiviral effector functions. Type 1 IFN also promotes DC maturation and contributes to potent antiviral T cell responses (Longhi et al., 2009Longhi M.P. Trumpfheller C. Idoyaga J. Caskey M. Matos I. Kluger C. Salazar A.M. Colonna M. Steinman R.M. Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant.J. Exp. Med. 2009; 206: 1589-1602Crossref PubMed Scopus (191) Google Scholar). 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Unlike other viruses that do induce type 1 IFN, retroviruses are generally believed not to encode specific proteins that block innate immune signaling, although some recent reports suggest that HIV-1 disrupts RIG-I and a downstream transcription factor, interferon regulatory factor (IRF3) (Solis et al., 2011Solis M. Nakhaei P. Jalalirad M. Lacoste J. Douville R. Arguello M. Zhao T. Laughrea M. Wainberg M.A. Hiscott J. RIG-I-mediated antiviral signaling is inhibited in HIV-1 infection by a protease-mediated sequestration of RIG-I.J. Virol. 2011; 85: 1224-1236Crossref PubMed Scopus (35) Google Scholar; Doehle et al., 2012aDoehle B.P. Chang K. Fleming L. McNevin J. Hladik F. McElrath M.J. Gale Jr., M. Vpu-deficient HIV strains stimulate innate immune signaling responses in target cells.J. Virol. 2012; 86: 8499-8506Crossref PubMed Scopus (5) Google Scholar, Doehle et al., 2012bDoehle B.P. Chang K. Rustagi A. McNevin J. McElrath M.J. Gale Jr., M. Vpu mediates depletion of interferon regulatory factor 3 during HIV infection by a lysosome-dependent mechanism.J. Virol. 2012; 86: 8367-8374Crossref PubMed Scopus (11) Google Scholar). Further, under particular experimental conditions in vitro, aborted HIV-1 reverse transcripts in CD4+ T cells have been shown to activate apoptosis and inflammation in a process that involves caspase-3 and caspase-1 (Doitsh et al., 2010Doitsh G. Cavrois M. Lassen K.G. Zepeda O. Yang Z. Santiago M.L. Hebbeler A.M. Greene W.C. Abortive HIV infection mediates CD4 T cell depletion and inflammation in human lymphoid tissue.Cell. 2010; 143: 789-801Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Important information concerning innate immune detection of retroviruses has been obtained by studying rare instances where adaptive immune control of retroviral infection has been observed. Specific strains of inbred mice such as I/LnJ and C57BL/6J, for example, are resistant to infection with the murine retroviruses Murine Leukemia Virus (MuLV) and Mouse Mammary Tumor Virus (MMTV) via both humoral and cellular mechanisms. This experimental system offers an opportunity to identify the innate immune PRRs that contribute to these protective, antiretroviral acquired immune responses. The protective antibody responses to both viruses in these mice were TLR7 dependent (Kane et al., 2011bKane M. Case L.K. Wang C. Yurkovetskiy L. Dikiy S. Golovkina T.V. Innate immune sensing of retroviral infection via Toll-like receptor 7 occurs upon viral entry.Immunity. 2011; 35: 135-145Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar), but induction of protective CTL responses was dependent on a separate, yet to be defined, innate immune detection pathway (Browne and Littman, 2009Browne E.P. Littman D.R. Myd88 is required for an antibody response to retroviral infection.PLoS Pathog. 2009; 5: e1000298Crossref PubMed Scopus (27) Google Scholar; Kane et al., 2011bKane M. Case L.K. Wang C. Yurkovetskiy L. Dikiy S. Golovkina T.V. Innate immune sensing of retroviral infection via Toll-like receptor 7 occurs upon viral entry.Immunity. 2011; 35: 135-145Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar). The importance of innate immune detection of retroviruses for subsequent acquired immunity was also demonstrated
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