Human Dendritic Cells Transduced with Herpes Simplex Virus Amplicons Encoding Human Immunodeficiency Virus Type 1 (HIV-1) gp120 Elicit Adaptive Immune Responses from Human Cells Engrafted into NOD/SCID Mice and Confer Partial Protection against HIV-1 Challenge

Gorantla, Santhi; Santos, Kathlyn; Meyer, V.S.E.; Dewhurst, Stephen; Bowers, William J.; Federoff, Howard J.; Gendelman, Howard Eliot; Poluektova, Larisa Y.

doi:10.1128/jvi.79.4.2124-2132.2005

Cited by 38 publications

(28 citation statements)

References 62 publications

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“…Among the appealing characteristics of these vectors are their large insert capacity, favorable safety profile and broad cellular/tissue tropism -which extends to antigen presenting cells, such as dendritic cells (DC) [3]. As a result, helper-free HSV-1 amplicons encoding mammalian or microbial proteins can elicit strong, antigenspecific immune responses, and may have utility in a range of applications, including cancer treatment and prophylactic vaccination against pathogens such as human immunodeficiency virus type-1 (HIV-1) [3][4][5][6][7][8][9][10].…”

Section: Introductionmentioning

confidence: 99%

“…To date, most studies involving HSV-1 amplicon-vectored vaccines have relied on the use of the HSV-1 immediate early 4/5 promoter (HSV IE4/5) [3][4][5]7]. However, it is unclear whether this is the ideal transcriptional control element for use in vaccine studies -especially since the activity of this promoter is strongly influenced by the HSV-1 tegument protein, VP16 [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 Gag

Santos¹,

Duke²,

Rodríguez-Colón³

et al. 2007

Vaccine

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Helper-free herpes simplex virus type-1 (HSV-1) amplicon vectors elicit robust immune responses to encoded proteins, including human immunodeficiency virus type-1 (HIV-1) antigens. To improve this vaccine delivery system, seven amplicon vectors were constructed, each encoding HIV-1 Gag under the control of a different promoter. Gag expression levels were analyzed in murine and human cell lines, as well as in biopsied tissue samples from injected mice; these data were then compared with Gag-specific T cell responses in BALB/c mice. The magnitude of the amplicon-induced immune response was found to correlate strongly with the level of Gag production both in vitro and in vivo. Interestingly, the best correlation of the strength of the amplicon-induced immune response was with antigen expression in cultured DC rather than expression at the tissue site of injection or in cultured cell lines. These findings may have implications for the generation of improved HSV-1 amplicon vectors for HIV-1 vaccine delivery.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 Gag

Santos¹,

Duke²,

Rodríguez-Colón³

et al. 2007

Vaccine

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“…A more successful strategy to humanize mice has been to engraft human immune cells and/or tissues into immunodeficient severe combined immunodeficiency (SCID) or nonobese diabetic (NOD)/SCID mice that are unable to reject xenogeneic grafts (39,42,57). Early versions of humanized mice supported productive HIV infec-tion and allowed investigators to begin to address important questions in HIV biology in vivo (23,40,(43)(44)(45). More recently, human cord blood or fetal liver CD34 ϩ cells have been used to reconstitute Rag2 Ϫ/Ϫ interleukin-2 receptor ␥ chaindeficient (␥ c Ϫ/Ϫ ) and NOD/SCID/␥ c Ϫ/Ϫ mice, resulting in higher levels of sustained human immune cell engraftment (27,29,61).…”

mentioning

confidence: 99%

Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice

Brainard

Seung

Frahm

et al. 2009

J Virol

251

339

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The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34؉ fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/ macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4 ؉ T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIVspecific CD4؉ and CD8 ؉ T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4 ؉ and CD8 ؉ T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4 ؉ cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.

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“…Herpes simplex virus type-1 (HSV-1) with deletions in the Δγ 1 34.5 gene is replication-competent but is aneurovirulent [23]. Attenuated HSV-1 recombinants are attractive as HIV-1 vaccine vectors for multiple reasons: i) herpesvirus vectors can infect dendritic cells and stimulate potent, longlasting CMI responses [24][25][26][27][28]; ii) attenuated HSV can establish latency and reactivate with the potential to prolong an immune response [29,30]; iii) several nonessential genes can be deleted and replaced with multiple foreign gene inserts (up to 30 kb) [31]; vi) HSV Δγ 1 34.5 viruses have been safe during human use in clinical trials, including intracranial injection at high doses [32][33][34][35]; and v) although prior immunity to HSV has a variable effect on vector efficacy in gene therapy applications, it does not impair either antibody or CMI responses elicited against immunogens expressed from HSV vectors [36][37][38][39].…”

Section: Introductionmentioning

confidence: 99%

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

Parker

Rottinghaus

Zajac

et al. 2007

Vaccine

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We have constructed a replication competent, γ 1 34.5-deleted Herpes Simplex Virus type 1 (HSV-1) vector (J200) that expresses the gag gene from Human Immunodeficiency Virus type-1, primary isolate 89.6 (HIV-1 89.6 ), as a candidate vaccine for HIV-1. J200 replicates in vitro, resulting in abundant Gag protein production and accumulation in the extracellular media. Immunization of Balb/ c mice with a single intraperitoneal injection of J200 elicited strong Gag-specific CD8 responses, as measured by intracellular IFN-γ staining and flow cytometry analysis. Responses were highest between 6 weeks and 4 months, but persisted at 9 months post-immunization, the last time-point evaluated. These data highlight the potential utility of neuroattenuated, replication-competent HSV-1 vectors for delivery of HIV-1 immunogens.

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Human Dendritic Cells Transduced with Herpes Simplex Virus Amplicons Encoding Human Immunodeficiency Virus Type 1 (HIV-1) gp120 Elicit Adaptive Immune Responses from Human Cells Engrafted into NOD/SCID Mice and Confer Partial Protection against HIV-1 Challenge

Abstract: Small-animal models are needed to test human immunodeficiency virus (HIV

Cited by 38 publications

References 62 publications

Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 Gag

Effect of promoter strength on protein expression and immunogenicity of an HSV-1 amplicon vector encoding HIV-1 Gag

Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice

HIV-189.6 Gag expressed from a replication competent HSV-1 vector elicits persistent cellular immune responses in mice

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