HIV-1 Tat-coated nanoparticles result in enhanced humoral immune responses and neutralizing antibodies compared to alum adjuvant

AbstractA small number of HIV-1 infected individuals develop broadly neutralizing-antibodies to the virus (bNAbs). These antibodies are protective against infection in animal models. However, they only emerge 1 - 3 years after infection, and show a number of highly unusual features including exceedingly high levels of somatic mutations. It is therefore not surprising that elicitation of protective immunity to HIV-1 has not yet been possible. Here we show that mature, primary mouse and human B cells can be editedin vitrousing CRISPR/Cas9 to express mature bNAbs from the endogenousIghlocus. Moreover, edited B cells retain the ability to participate in humoral immune responses. Immunization with cognate antigen in wild type mouse recipients of edited B cells elicits bNAb titers that neutralize HIV-1 at levels associated with protection against infection. This approach enables humoral immune responses that may be difficult to elicit by traditional immunization.One-sentence summaryB cells edited by CRISPR/Cas9 to produce antibodies participate in humoral immune reactions and secrete neutralizing serum titers of anti-HIV bNAbs.

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HIV-specific humoral immune responses by CRISPR/Cas9-edited B cells

Journal of Experimental Medicine ◽

10.1084/jem.20190287 ◽

2019 ◽

Vol 216 (6) ◽

pp. 1301-1310 ◽

Cited By ~ 19

Author(s):

Harald Hartweger ◽

Andrew T. McGuire ◽

Marcel Horning ◽

Justin J. Taylor ◽

Pia Dosenovic ◽

...

Keyword(s):

B Cells ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Wild Type Mouse ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Human B Cells ◽

Primary Mouse ◽

Hiv 1

A small number of HIV-1–infected individuals develop broadly neutralizing antibodies to the virus (bNAbs). These antibodies are protective against infection in animal models. However, they only emerge 1–3 yr after infection, and show a number of highly unusual features including exceedingly high levels of somatic mutations. It is therefore not surprising that elicitation of protective immunity to HIV-1 has not yet been possible. Here we show that mature, primary mouse and human B cells can be edited in vitro using CRISPR/Cas9 to express mature bNAbs from the endogenous Igh locus. Moreover, edited B cells retain the ability to participate in humoral immune responses. Immunization with cognate antigen in wild-type mouse recipients of edited B cells elicits bNAb titers that neutralize HIV-1 at levels associated with protection against infection. This approach enables humoral immune responses that may be difficult to elicit by traditional immunization.

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Antibodies from rabbits immunized with HIV-1 clade B SOSIP trimers can neutralize multiple clade B viruses by destabilizing the envelope glycoprotein

Journal of Virology ◽

10.1128/jvi.00094-21 ◽

2021 ◽

Author(s):

M. M. van Haaren ◽

L. E. McCoy ◽

J. L. Torres ◽

W Lee ◽

C. A. Cottrell ◽

...

Keyword(s):

Immune Responses ◽

Envelope Glycoprotein ◽

Neutralizing Antibodies ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Immunization Strategies ◽

Clade B ◽

Humoral Responses ◽

Neutralization Ability ◽

Hiv 1

The high HIV-1 viral diversity is a formidable hurdle for the development of an HIV-1 vaccine. Elicitation of broadly neutralizing antibodies (bNAbs) would offer a solution, but so far immunization strategies have failed to elicit bNAbs efficiently. To overcome the obstacles, it is important to understand the immune responses elicited by current HIV-1 envelope glycoprotein (Env) immunogens. To gain more insight, we characterized monoclonal antibodies (mAbs) isolated from rabbits immunized with Env SOSIP trimers based on the clade B isolate AMC008. Four rabbits that were immunized three times with AMC008 trimer developed robust autologous and sporadic low-titer heterologous neutralizing responses. Seventeen AMC008 trimer-reactive mAbs were isolated using antigen-specific single B cell sorting. Four of these mAbs neutralized the autologous AMC008 virus and several other clade B viruses. When visualized by electron microscopy, the complex of the neutralizing mAbs with the AMC008 trimer showed binding to the gp41 subunit with unusual approach angles and we observed that their neutralization ability depended on their capacity to induce Env trimer dissociation. Thus, AMC008 SOSIP trimer immunization induced clade B neutralizing mAbs with unusual approach angles with neutralizing effects that involve trimer destabilization. Optimizing these responses might provide an avenue to the induction of trimer dissociating bNAbs. IMPORTANCE Roughly 32 million people have died as a consequence of HIV-1 infection since the start of the epidemic and still 1.7 million people get infected with HIV-1 annually. Therefore, a vaccine to prevent HIV-1 infection is urgently needed. Current HIV-1 immunogens are not able to elicit the broad immune responses needed to provide protection against the large variation of HIV-1 strains circulating globally. A better understanding of the humoral immune responses elicited by immunization with state-of-the-art HIV-1 immunogens should facilitate the design of improved HIV-1 vaccine candidates. We identified antibodies with the ability to neutralize multiple HIV-1 viruses by destabilization of the envelope glycoprotein. Their weak but consistent cross-neutralization ability indicates the potential of this epitope to elicit broad responses. The trimer-destabilizing effect of the neutralizing mAbs combined with detailed characterization of the neutralization epitope can be used to shape the next generation of HIV-1 immunogens to elicit improved humoral responses after vaccination.

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Scarcity or Absence of Humoral Immune Responses in the Plasma and Cervicovaginal Lavage Fluids of Heavily HIV-1-Exposed But Persistently Seronegative Women

AIDS Research and Human Retroviruses ◽

10.1089/aid.2010.0169 ◽

2011 ◽

Vol 27 (5) ◽

pp. 469-486 ◽

Cited By ~ 35

Author(s):

Jiri Mestecky ◽

Peter F. Wright ◽

Lucia Lopalco ◽

Herman F. Staats ◽

Pamela A. Kozlowski ◽

...

Keyword(s):

Immune Responses ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Cervicovaginal Lavage ◽

Hiv 1

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The vaccinia-based Sementis Copenhagen Vector COVID-19 vaccine induces broad and durable cellular and humoral immune responses

10.1101/2021.09.06.459206 ◽

2021 ◽

Author(s):

Preethi Eldi ◽

Tamara H Cooper ◽

Natalie A Prow ◽

Liang Liu ◽

Gary K Heinemann ◽

...

Keyword(s):

Immune Responses ◽

Neutralizing Antibodies ◽

First Generation ◽

Neutralizing Antibody ◽

Immune Memory ◽

Antibody Activity ◽

Post Vaccination ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Heterologous Boost

The ongoing COVID-19 pandemic perpetuated by SARS-CoV-2 variants, has highlighted the continued need for broadly protective vaccines that elicit robust and durable protection. Here, the vaccinia virus-based, replication-defective Sementis Copenhagen Vector (SCV) was used to develop a first-generation COVID-19 vaccine encoding the spike glycoprotein (SCV-S). Vaccination of mice rapidly induced polyfunctional CD8 T cells with cytotoxic activity and robust Th1-biased, spike-specific neutralizing antibodies, which are significantly increased following a second vaccination, and contained neutralizing activity against the alpha and beta variants of concern. Longitudinal studies indicated neutralizing antibody activity was maintained up to 9 months post-vaccination in both young and aging mice, with durable immune memory evident even in the presence of pre-existing vector immunity. This immunogenicity profile suggests a potential to expand protection generated by current vaccines in a heterologous boost format, and presents a solid basis for second-generation SCV-based COVID-19 vaccine candidates incorporating additional SARS-CoV-2 immunogens.

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Induction of Humoral Immune Responses following Vaccination with Envelope-Containing, Formaldehyde-Treated, Thermally Inactivated Human Immunodeficiency Virus Type 1

Journal of Virology ◽

10.1128/jvi.79.8.4927-4935.2005 ◽

2005 ◽

Vol 79 (8) ◽

pp. 4927-4935 ◽

Cited By ~ 27

Author(s):

B. Poon ◽

J. T. Safrit ◽

H. McClure ◽

C. Kitchen ◽

J. F. Hsu ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Thermal Treatment ◽

Immune Responses ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The lack of success of subunit human immunodeficiency virus type 1 (HIV-1) vaccines to date suggests that multiple components or a complex virion structure may be required. We previously demonstrated retention of the major conformational epitopes of HIV-1 envelope following thermal treatment of virions. Moreover, antibody binding to some of these epitopes was significantly enhanced following thermal treatment. These included the neutralizing epitopes identified by monoclonal antibodies 1b12, 2G12, and 17b, some of which have been postulated to be partially occluded or cryptic in native virions. Based upon this finding, we hypothesized that a killed HIV vaccine could be derived to elicit protective humoral immune responses. Shedding of HIV-1 envelope has been described for some strains of HIV-1 and has been cited as one of the major impediments to developing an inactivated HIV-1 vaccine. In the present study, we demonstrate that treatment of virions with low-dose formaldehyde prior to thermal inactivation retains the association of viral envelope with virions. Moreover, mice and nonhuman primates vaccinated with formaldehyde-treated, thermally inactivated virions produce antibodies capable of neutralizing heterologous strains of HIV in peripheral blood mononuclear cell-, MAGI cell-, and U87-based infectivity assays. These data indicate that it is possible to create an immunogen by using formaldehyde-treated, thermally inactivated HIV-1 virions to induce neutralizing antibodies. These findings have broad implications for vaccine development.

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