Dendritic Cell-Lysosomal-Associated Membrane Protein (LAMP) and LAMP-1-HIV-1 Gag Chimeras Have Distinct Cellular Trafficking Pathways and Prime T and B Cell Responses to a Diverse Repertoire of Epitopes

Mucosal nasal vaccine development, although ideal to protect from pathogens invading mucosally, is limited by the lack of specific adjuvant. We recently used P1, a conserved region of HIV-1 gp41-envelope glycoprotein, as efficient antigen in a prophylactic HIV-1 mucosal vaccine applied nasally. Herein, P1 immunomodulation properties were assessed on human nasal mucosal models by measuring induction of cytokine and chemokine production, intracellular signaling pathways, mucosal dendritic cell (DC) activation, and T cell proliferation. P1 adjuvant properties were evaluated by quantification of antigen-specific B cell responses against a model antigen in an in vitro immunization model. We now demonstrated that P1 has additional immunological properties. P1 initiates immune responses by inducing nasal epithelial cells to secrete the Th2-cytokine thymic stromal lymphopoietin (TSLP), a described mucosal adjuvant. Secreted TSLP activates, in turn, intracellular calcium flux and PAR-2-associated NFAT signaling pathway regulated by microRNA-4485. Thereafter, P1 induces mucosal dendritic cell maturation, secretion of TSLP in a TSLP-receptor (R)-dependent autocrine loop, but also IL-6, IL-10, IL-8, CCL20, CCL22, and MMP-9, and proliferation of CD4+ T cells. Finally, P1 acts as an adjuvant to stimulate antigen-specific B cell responses in vitro. Overall, P1 is a multi-functional domain with various immuno-modulatory properties. In addition to being a protective vaccine antigen for HIV prevention, P1 acts as adjuvant for other mucosal vaccines able to stimulate humoral and cellular antigen-specific responses.

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Rapid Development of gp120-Focused Neutralizing B Cell Responses during Acute Simian Immunodeficiency Virus Infection of African Green Monkeys

Journal of Virology ◽

10.1128/jvi.01564-15 ◽

2015 ◽

Vol 89 (18) ◽

pp. 9485-9498 ◽

Cited By ~ 5

Author(s):

Joshua D. Amos ◽

Jonathon E. Himes ◽

Lawrence Armand ◽

Thaddeus C. Gurley ◽

David R. Martinez ◽

...

Keyword(s):

B Cell ◽

Disease Progression ◽

Simian Immunodeficiency Virus ◽

Rapid Development ◽

Virus Transmission ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Siv Infection ◽

B Cell Responses ◽

Hiv 1

ABSTRACTThe initial phases of acute human immunodeficiency virus type 1 (HIV-1) infection may be critical for development of effective envelope (Env)-specific antibodies capable of impeding the establishment of the latent pool of HIV-1-infected CD4+T cells, preventing virus-induced immune hyperactivation to limit disease progression and blocking vertical virus transmission. However, the initial systemic HIV-1 Env-specific antibody response targets gp41 epitopes and fails to control acute-phase viremia. African-origin, natural simian immunodeficiency virus (SIV) hosts do not typically progress to AIDS and rarely postnatally transmit virus to their infants, despite high milk viral loads. Conversely, SIV-infected rhesus macaques (RMs), Asian-origin nonnatural SIV hosts, sustain pathogenic SIV infections and exhibit higher rates of postnatal virus transmission. In this study, of acute SIV infection, we compared the initial systemic Env-specific B cell responses of AGMs and RMs in order to probe potential factors influencing the lack of disease progression observed in AGMs. AGMs developed higher-magnitude plasma gp120-specific IgA and IgG responses than RMs, whereas RMs developed more robust gp140-directed IgG responses. These gp120-focused antibody responses were accompanied by rapid autologous neutralizing responses during acute SIV infection in AGMs compared to RMs. Moreover, acute SIV infection elicited a higher number of circulating Env-specific memory B cells in peripheral blood of AGMs than in the blood of RMs. These findings indicate that AGMs have initial systemic Env-specific B cell responses to SIV infection distinct from those of a nonnatural SIV host, resulting in more functional SIV-specific humoral responses, which may be involved in impairing pathogenic disease progression and minimizing postnatal transmission.IMPORTANCEDue to the worldwide prevalence of HIV-1 infections, development of a vaccine to prevent infection or limit the viral reservoir remains an important goal. HIV-1-infected humans, as well as SIV-infected nonnatural SIV hosts, develop pathogenic infections and readily transmit the virus to their infants. Conversely, natural SIV hosts do not develop pathogenic infections and rarely transmit the virus to their infants. The immunologic factors contributing to these favorable outcomes in natural SIV hosts could prove invaluable for directing HIV-1 vaccine and therapy design. This study identified distinctions in the specificity and function of the initial systemic SIV envelope-specific B cell response that developed during acute SIV infection in natural and nonnatural SIV host species. Identification of distinct acute B cell responses in natural SIV hosts may inform vaccine strategies seeking to elicit similar responses prior to or during the initial phases of acute HIV-1 infection.

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Optimizing delivery of HIV-1 conserved region-derived immunogen for induction of T and B cell responses in rhesus macaques

Retrovirology ◽

10.1186/1742-4690-9-s2-p31 ◽

2012 ◽

Vol 9 (Suppl 2) ◽

pp. P31

Author(s):

M Rosario ◽

G Koopman ◽

A Mbewe-Mvula ◽

ML Knudsen ◽

ED Quakkelaar ◽

...

Keyword(s):

B Cell ◽

Rhesus Macaques ◽

Cell Responses ◽

Conserved Region ◽

B Cell Responses ◽

Hiv 1

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P04-48. HIV-1 envelope induces memory B cell responses that correlate with plasma antibody levels after gp120 protein vaccination or chronic HIV-1 infection

Retrovirology ◽

10.1186/1742-4690-6-s3-p76 ◽

2009 ◽

Vol 6 (S3) ◽

Author(s):

M Bonsignori ◽

MA Moody ◽

RJ Parks ◽

TM Holl ◽

G Kelsoe ◽

...

Keyword(s):

B Cell ◽

Memory B Cell ◽

Cell Responses ◽

Gp120 Protein ◽

Plasma Antibody ◽

B Cell Responses ◽

Antibody Levels ◽

Hiv 1

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B Cell Responses to HIV Antigen Are a Potent Correlate of Viremia in HIV-1 Infection and Improve with PD-1 Blockade

PLoS ONE ◽

10.1371/journal.pone.0084185 ◽

2013 ◽

Vol 8 (12) ◽

pp. e84185 ◽

Cited By ~ 21

Author(s):

Katherine J. Nicholas ◽

Emily K. Zern ◽

Louise Barnett ◽

Rita M. Smith ◽

Shelly L. Lorey ◽

...

Keyword(s):

B Cell ◽

Cell Responses ◽

Hiv Antigen ◽

B Cell Responses ◽

Hiv 1

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Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected Individuals

Journal of Virology ◽

10.1128/jvi.05363-11 ◽

2011 ◽

Vol 85 (21) ◽

pp. 11502-11519 ◽

Cited By ~ 145

Author(s):

G. D. Tomaras ◽

J. M. Binley ◽

E. S. Gray ◽

E. T. Crooks ◽

K. Osawa ◽

...

Keyword(s):

B Cell ◽

Cell Responses ◽

B Cell Responses ◽

Hiv 1

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P12-12. Analysis of antibody and B cell responses following inoculation with computationally designed HIV-1 2F5 epitope scaffold proteins

Retrovirology ◽

10.1186/1742-4690-6-s3-p178 ◽

2009 ◽

Vol 6 (S3) ◽

Author(s):

P Dosenovic ◽

J Guenaga ◽

G Ofek ◽

D Baker ◽

W Schief ◽

...

Keyword(s):

B Cell ◽

Scaffold Proteins ◽

Cell Responses ◽

B Cell Responses ◽

Hiv 1

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P05-07. Evaluation of peripheral and bone marrow B cell responses in rhesus macaques after immunization with soluble HIV-1 gp140 trimers

Retrovirology ◽

10.1186/1742-4690-6-s3-p83 ◽

2009 ◽

Vol 6 (S3) ◽

Author(s):

C Sundling ◽

M Soldemo ◽

B Chakrabarti ◽

MN Forsell ◽

K Loré ◽

...

Keyword(s):

Bone Marrow ◽

B Cell ◽

Rhesus Macaques ◽

Cell Responses ◽

B Cell Responses ◽

Hiv 1

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Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site

Journal of Virology ◽

10.1128/jvi.00811-17 ◽

2017 ◽

Vol 91 (19) ◽

Cited By ~ 4

Author(s):

Willy M. J. M. Bogers ◽

Susan W. Barnett ◽

Herman Oostermeijer ◽

Ivonne G. Nieuwenhuis ◽

Niels Beenhakker ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Binding Site ◽

T Helper ◽

Cell Responses ◽

Cd4 Receptor ◽

Cd4 Binding Site ◽

B Cell Responses ◽

Hiv Envelope ◽

Hiv 1

ABSTRACT Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4+ T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell (P < 0.001) response kinetics and superior ADCC (P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier (P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.

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