SUPPLEMENT ARTICLE

Recent Advances in Humanized Mice: Accelerating the Development of an HIV Vaccine Andrew M. Tager,1,2 Michael Pensiero,3 and Todd M. Allen2 1

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School; 2Ragon Institute of MGH, MIT, and Harvard, Boston, Massachusetts and 3Vaccine Translational Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Keywords.

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Recent advances in the development of humanized mice hold great promise to advance our understanding of protective immunity to human immunodeficiency virus (HIV) infection and to aid in the design of an effective HIV vaccine. This supplement of the Journal of Infectious Diseases summarizes work in the humanized mouse model presented at an HIV Humanized Mouse workshop in Boston, Massachusetts, in November 2012, including recent advances in the development of humanized mice, the trafficking of human immune cells following mucosal HIV transmission, the role of immune activation and Toll-like receptor agonists in the control of HIV, the induction and efficacy of HIV-specific cellular and humoral immune responses, and the preclinical modeling of novel anti-HIV therapeutics. Many gaps remain in our understanding of how to design an effective HIV vaccine and novel therapeutics to eliminate the viral reservoir. Promising early results from studies in humanized mice suggest great potential and enthusiasm for this model to accelerate these critical areas of HIV research. HIV; humanized mice; vaccine; CD8+ T cells; CTL; antibodies.

In November 2012, a symposium on humanized mouse models of human immunodeficiency virus (HIV) infection presented recent studies exploring the potential of these models to advance the study of HIV vaccine design. The symposium was jointly sponsored by the Ragon Institute of MGH, MIT, and Harvard; the Harvard Center for AIDS Research; and the National Institutes of Allergy and Infectious Diseases. In this supplement of the Journal, we provide an overview of some of these recent advances in the application of humanized mice for the study of HIV, including the trafficking of HIVspecific human immune cells following transmission; innate, cellular, and humoral immune responses to HIV; and the potential of humanized mice to model novel anti-HIV therapeutics. These and other recent

Correspondence: Todd M. Allen, PhD, Ragon Institute of MGH, MIT, and Harvard, 400 Technology Sq, Cambridge, MA 02139 ([email protected]). The Journal of Infectious Diseases 2013;208(S2):S121–4 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: [email protected]. DOI: 10.1093/infdis/jit451

studies in the field illustrate the potential of humanized mouse models to improve our understanding of the early events of HIV infection and of HIV-specific immunity, to accelerate HIV vaccine design. Although interventional programs, antiretrovirals, and microbicides have had recent successes in preventing the spread of HIV, there remains a great need for an effective HIV vaccine capable of inducing a sufficiently robust and directed immune response to block HIV infection. The recent RV144 Thai trial, in which >16 000 individuals participated in a study of the efficacy of Sanofi Pasteur’s recombinant canarypox virus (ALVAC-HIV) combined with engineered HIV gp120 surface proteins (AIDSVAX B/E), provided the first hint in humans that an HIV vaccine might be capable of preventing HIV infection, albeit transiently [1]. Paradoxically, this vaccine failed to induce the expected correlates of immune protection against HIV: strong, broadly neutralizing antibodies, and cellular immune responses against conserved regions of the virus. Rather, recent studies suggest that a possible correlate of protection may be binding antibody responses to the V1/V2 regions of gp120 [2, 3]. Therefore, despite the potential success of the RV144 trial, many questions Humanized Mice and HIV Vaccine



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Deruaz et al [27] and Murooka et al [28] describe recent work to explore vaginal HIV transmission and dissemination in humanized mice and the importance of immune cell trafficking to this process. Immune activation is emerging as a strong risk factor for both HIV acquisition and disease progression [29–31]. Recent analyses from the CAPRISA 004 tenofovir microbicide gel trial reveal that women who acquired HIV exhibited higher levels of systemic innate immune activation (with respect to both soluble cytokines and innate natural killer cells) before infection than those who did not become infected [30, 31]. Similarly, during chronic infection the level of CD8+ T-cell activation is a better predictor of the rate of disease progression, compared with HIV type 1 load alone [29]. Given the important role of innate immune responses in regulating T-cell activation, here Chang et al [32] provide insight into the reconstitution of innate immunity in humanized mouse models and the potential of these models to elucidate the role of innate immunity in the control of HIV. The induction of a persistent and protective immune response to HIV will ultimately require both robust cellular and humoral immune responses. The targeting of highly conserved region of the virus, whether by broadly neutralizing antibodies or effective CD8+ T-cell responses, will be critical for immune control [4, 33]. The development of a small-animal model capable of mimicking human immune responses to HIV targets (vs SIV targets in the macaque model) would therefore provide a critical tool for assessing the efficacy of vaccine candidates. Here, Dudek et al [34] summarize their recent work detailing human HIV-specific CD8+ T-cell responses in BLT mice and the ability of this model to accurately recapitulate the specificity of human responses to HIV. Similarly, Seung et al [35] report on the potential of this model to also elicit human HIVspecific antibody responses during the acute phase of infection. Critically determining the extent to which BLT mice can recapitulate the magnitude, breadth, and specificity of human immune responses to HIV represents an important first step in accessing the potential for this model to accurately elicit vaccine-induced immunity to HIV. Finally, recent case studies hint at the possibility of eradicating HIV infections in the future through stem cell–based therapies or other novel therapeutic approaches [36, 37]. A humanized mouse model capable of supporting replication-competent HIV in latently infected CD8+ T cells, as recently demonstrated by Choudhary et al [38], could significantly accelerate preclinical studies aimed at targeting the viral reservoir. Here Hofer et al [39] describe their preclinical modeling of a novel zincfinger nuclease strategy to block the expression of the key HIV coreceptor CCR5 in humanized mice and the potential of this and similar approaches to engineer an HIV-resistant immune system. The enormous breadth of recent studies in humanized mice underscores the widespread enthusiasm for these chimeric

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as to how to effectively induce protective immunity to HIV in humans remain unanswered. The development of a small-animal model capable of accurately recapitulating the initial route and spread of HIV through mucosal tissues and the early innate and adaptive immune responses to HIV would greatly accelerate HIV vaccine testing. Furthermore, the ability to design and test the efficacy of various adjuvants and HIV vaccine antigens geared toward the targeting of critical regions of HIV could provide key insights into how best to design potent vaccines capable of most effectively crippling HIV [4–7]. Since the generation of the CB17-Prkdcscid severe combined immunodeficiency (SCID) mouse model by Bosma et al in 1983 [8], there have been numerous improvements to this small-animal model for human disease. Modifications leading to improved engraftment of human immune cells and/or tissues have included increases in the extent of immunodeficiency of the recipient mice [9, 10] and improvements in the delivery of adult human peripheral blood mononuclear cells, hematopoietic stem cells, and/or fetal tissues [11, 12]. In 1988, McCune et al demonstrated the potential of humanized mice for the study HIV infection through generation of SCID-hu mice, in which human fetal liver cells and thymus and lymph node tissues were transplanted into SCID mice [13, 14]. Recent reviews by Shultz et al and Akkina provide comprehensive overviews of the development of these and other humanized mouse models and their potential application to the study of human diseases [15, 16], including the more recent humanized bone marrow, liver, and thymus (BLT)–transplantation mouse model that appears to robustly reconstitute human immunity [17–22]. In another recent review, Brehm et al [23] further discuss recent breakthroughs in the development of various mouse models capable of supporting xenotransplantation of human immune cells and tissues, as well as recent approaches to enhance human innate and adaptive immunity in these models for the study of human infectious diseases. Recent vaccine studies in nonhuman primates suggest that vaccine-induced immunity has the potential not only to improve immune control of HIV but to also block infection. In the rhesus macaque model, the induction of Env-specific antibody responses by an adenovirus/poxvirus vector–based vaccine was associated with protection against acquisition following lowdose mucosal exposure to simian immunodeficiency virus (SIV) [24]. Similarly, Hansen et al recently demonstrated that vaccination with a cytomegalovirus vector containing SIV antigens induced high levels of CD8+ T-cell responses near the site of infection, in this case in rectal draining lymph nodes, that were capable of producing sterilizing immunity shortly after peak viremia [25, 26]. Given these recent successes and those of the aforementioned RV144 Thai trial, to actually prevent HIV infection, then to be most useful animal models of HIV infection will need to mimic the early events of HIV acquisition and dissemination, especially at mucosal surfaces. In their reviews,

models in efforts to accelerate many areas of biomedical research. The articles in this supplement describe current insights into how some of the recent advancements in humanized mouse models may help in the development of an effective HIV vaccine. As additional improvements to these models are identified, including methods to reduce graft-versus-host disease [22, 40, 41], the application of these models will continue to expand. Further studies exploring the efficacy of contemporary HIV vaccine vectors and adjuvants in humanized mice and the ability of these models to effectively recapitulate key attributes of mucosal HIV transmission will help to gauge their usefulness for direct testing of HIV vaccine candidates. If these studies are successful, they will provide an important next step in the development of an informative animal model capable of investigating the pathogenesis of HIV itself and the development of human immunity to this virus.

Financial support. This work was supported by the National Institute of Allergy and Infectious Diseases (grants R01-AI090698 and HIVRAD P01-AI104715 to T. M. A.) and the Harvard University Center for AIDS Research (grant P30-AI060354). Attendance at the Humanized Mouse Meeting was funded by the Harvard University Center for AIDS Research; the National Institute of Allergy and Infectious Diseases, National Institutes of Health; and the Ragon Institute of MGH, MIT, and Harvard. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Notes

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Recent advances in humanized mice: accelerating the development of an HIV vaccine.

Recent advances in the development of humanized mice hold great promise to advance our understanding of protective immunity to human immunodeficiency ...
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