Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques

Ng, Cherie; Jaworski, Juan Pablo; Jayaraman, Pushpa; Sutton, William F.; Delio, Patrick; Kuller, LaRene; Anderson, David; Landucci, Gary; Richardson, Barbra A.; Burton, Dennis R.; Forthal, Donald N.; Haigwood, Nancy L.

doi:10.1038/nm.2233

Cited by 126 publications

(130 citation statements)

References 20 publications

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“…12 In addition, we have shown recently that short neutralizing mAb-based immunotherapies may exert immunomodulatory effects translating into life-long immune protection (see end of "Introduction"), [20][21][22][23][24] which has potentially important consequences for treating life-threatening viral diseases in humans. The recent demonstration that passive neutralizing mAbs could not only control viremia in young macaques infected with a hybrid simian HIV strain, but also enhance B-cell responses in a perinatal setting 16 further supports this concept. Similar vaccine-like effects were also documented recently in 2 cancer models immunotherapy treated with mAbs directed to tumor cell membrane proteins.…”

Section: Introductionmentioning

confidence: 84%

“…14 Many chronic infections have also been targeted. Several human anti-HIV mAbs have been tested in nonhuman primates (see Hessell et al 15 and Ng et al 16 ) and in clinical trials, and broadly neutralizing human anti-HIV mAbs have been isolated recently. 17 Several human anti-HCV mAbs have also been developed recently, 18 some of which are currently being tested in the clinical setting.…”

Section: Introductionmentioning

confidence: 99%

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Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Nasser

Pelegrin

Plays

et al. 2013

Blood

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Key Points• Mab-based immunotherapy prevents Treg expansion and limits immunosuppressive activity.Regulatory T cells (Tregs) down-regulate immunity and are associated with chronic viral infections, suggesting that their inhibition might be used to treat life-threatening diseases. Using the FrCas E mouse retroviral model, we have recently shown that short mAb-based immunotherapies can induce life-long protective immunity. This finding has a potentially important therapeutical impact because mAbs are increasingly used to treat severe viral infections. We now report that poor anti-FrCas E immunity in infected mice is due to Treg expansion in secondary lymphoid organs because depletion of Tregs restored humoral and cytotoxic T lymphocyte (CTL) antiviral responses. Kinetic analyses show that Treg expansion is not a consequence of chronicity, but rather is associated with viral spread. Moreover, Treg adoptive transfers indicate that production of the immunosuppressive cytokine IL-10 is essential for preventing a protective immune response. Finally, treatment of infected mice with a virus-neutralizing IgG2a shortly after infection prevents Treg expansion and limits immunosuppressive activity. This effect is rapid, necessary for the development of protective immunity, and depends on mAb effector functions. Therefore, manipulating Tregs may be necessary to confer robust antiviral immunity in the context of mAb-based therapy. This concept likely applies to cancer treatment because vaccine-like effects of mAbs have also been observed in certain cancer immunotherapies. (Blood. 2013;121(7):1102-1111) IntroductionRegulatory T cells (Tregs) are a subset of CD4 ϩ T lymphocytes down-regulating the immune system. 1 They are the key modulators of the establishment and/or maintenance of viral chronicity and constitute a barrier to efficient vaccination and immunotherapy strategies. 2 The implication of Tregs in chronic viral infection was first described in mice infected with the Friend virus complex (FV) 3 and was then extended to other persistent viruses, including HIV, 4 HBV, 5,6 HCV, 5,6 EBV, 7 LCMV, 8 HSV, 9 and HPVs. 10 It is increasingly clear that controlling this immunosuppressive cell subset would have widespread clinical applications to fight lifethreatening viral diseases. 11 mAbs constitute the largest class of biotherapeutics. 12 Their main current applications are in cancer and inflammatory diseases, 12 but they also have an enormous potential to treat both acute and chronic severe viral infections. Although the first antiviral mAb to be commercialized (in 1998) was an anti-RSV to treat an infant respiratory disease, 13 many of the current antiviral mAbs have been developed more recently. 12 Illustrating this trend, humanized mAbs targeting diverse viruses (Ebola, WNV, CMV, human and avian influenza, SARS, Hanta, and Nipah) responsible for acute diseases have recently shown promising results in preclinical animal settings. Some of them are now undergoing clinical trials. 14 Many chronic infections have also been targ...

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Nasser

Pelegrin

Plays

et al. 2013

Blood

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“…This goal is supported by the overwhelming evidence of the capability of broadly neutralizing mAbs (bNmAbs) given prior to mucosal exposure in preventing viral infection in macaques using the chimeric simian/HIV (SHIV) bearing HIV env (2)(3)(4)(5). Neutralizing polyclonal Igs at high concentrations can block infection and have been shown to ameliorate disease pathogenesis in nonhuman primates (NHP) (6,7). Recently, bNmAbs used as therapeutic treatment during chronic infection in macaques and humanized mice led to rapid declines in plasma viremia and temporary viral suppression (8)(9)(10)(11).…”

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confidence: 99%

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Hessell

Malherbe

Pissani

et al. 2016

The Journal of Immunology

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Advancement in immunogen selection and vaccine design that will rapidly elicit a protective Ab response is considered critical for HIV vaccine protective efficacy. Vaccine-elicited Ab responses must therefore have the capacity to prevent infection by neutralization-resistant phenotypes of transmitted/founder (T/F) viruses that establish infection in humans. Most vaccine candidates to date have been ineffective at generating Abs that neutralize T/F or early variants. In this study, we report that coimmunizing rhesus macaques with HIV-1 gp160 DNA and gp140 trimeric protein selected from native envelope gene sequences (envs) induced neutralizing Abs against Tier 2 autologous viruses expressing cognate envelope (Env). The Env immunogens were selected from envs emerging during the earliest stages of neutralization breadth developing within the first 2 years of infection in two clade B–infected human subjects. Moreover, the IgG responses in macaques emulated the targeting to specific regions of Env known to be associated with autologous and heterologous neutralizing Abs developed within the human subjects. Furthermore, we measured increasing affinity of macaque polyclonal IgG responses over the course of the immunization regimen that correlated with Tier 1 neutralization. In addition, we report firm correlations between Tier 2 autologous neutralization and Tier 1 heterologous neutralization, as well as overall TZM-bl breadth scores. Additionally, the activation of Env-specific follicular helper CD4 T cells in lymphocytes isolated from inguinal lymph nodes of vaccinated macaques correlated with Tier 2 autologous neutralization. These results demonstrate the potential for native Env derived from subjects at the time of neutralization broadening as effective HIV vaccine elements.

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“…Several broadly neutralizing antibodies (bNAbs) to HIV-1 gp160 have been isolated, including a group that binds to gp120 (10)(11)(12)(13)(14)(15)(16)(17)(18) and a group that is specific for gp41 (19)(20)(21). Importantly, passive transfer of bNAbs to monkeys effectively protects them against simian-human immunodeficiency virus infection (22)(23)(24)(25)(26)(27)(28)(29)(30)(31), and it has therefore been proposed that vaccines that elicit such antibodies may be protective against infection in humans (1,2,(32)(33)(34).…”

mentioning

confidence: 99%

Enhanced HIV-1 neutralization by antibody heteroligation

Mouquet

Warncke

Scheid

et al. 2012

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

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Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti–HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation.

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Passive neutralizing antibody controls SHIV viremia and enhances B cell responses in infant macaques

Cited by 126 publications

References 20 publications

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

Achieving Potent Autologous Neutralizing Antibody Responses against Tier 2 HIV-1 Viruses by Strategic Selection of Envelope Immunogens

Enhanced HIV-1 neutralization by antibody heteroligation

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