Abstract
The generation of a vaccine against HIV-1 able to induce durable protective immunity continues a major challenge. The modest efficacy (31.2%) of the phase III RV144 clinical trial provided the first demonstration that a prophylactic HIV/AIDS vaccine is achievable but emphasized the need for further refinements of vaccine candidates, formulations, and immunization regimens. Here, we analyzed in mice the immunogenicity profile elicited by different homologous and heterologous prime/boost combinations using the modified rhabdovirus VSV-GP combined with DNA or poxviral NYVAC vectors, all expressing trimeric membrane-bound Env (gp145) of HIV-1 96ZM651 clade C, with or without purified gp140 protein component. In cultured cells infected with recombinant VSV-GP or NYVAC viruses, gp145 epitopes at the plasma membrane were recognized by human HIV-1 broadly neutralizing antibodies (bNAbs). In immunized mice, the heterologous combination of VSV-GP and NYVAC recombinant vectors improved the induction of HIV-1 Env-specific humoral and cellular immune responses compared to homologous prime/boost protocols. Specifically, the combination of VSV-GP in the prime and NYVAC in the boost induced higher HIV-1 Env-specific T cell (CD4/CD8 T cells and T follicular helper -Tfh- cells) immune responses compared to the use of DNA or NYVAC vectors in the prime and VSV-GP in the boost. Such enhanced T cell responses correlated with an enhancement of the Env-specific germinal center (GC) B cell population and with a heavily biased Env-specific response toward the Th1-associated IgG2a and IgG3 subclasses, while the other groups showed a Th2-associated IgG1 bias. In summary, our T and B cell population data demonstrated that VSV-GP-based vectors could be taken into consideration as an optimized immunogenic HIV-1 vaccine candidate component against HIV-1 when used for priming in heterologous combinations with the poxvirus vector NYVAC as a boost.
Highlights
Since the discovery of the Human Immunodeficiency Virus type 1 (HIV-1) as the causal agent of Acquired Immunodeficiency Syndrome (AIDS) in 1983 [1], many efforts have been performed to discontinue the HIV/AIDS pandemic
In an effort to optimize the HIV-1 immunization protocols, we have addressed the question whether VSV-GP and NYVAC vectors expressing trimeric and membrane-bound Env protein trigger superior and more balanced HIV-1specific T and B cell responses in mice when compared with the homologous vector combination, with or without a gp140 protein component, or when DNA was used during priming
To analyze whether the HIV-1 Env protein expressed by both VSV-GP-gp145 and NYVAC-gp145 recombinant viruses exhibits a membrane-bound trimeric conformation, we further evaluated by flow cytometry the affinity of a panel of broadly neutralizing antibodies (bNAbs) and non-NAbs to the HIV-1 gp145 protein expressed on the plasma membrane of VSV-GP-gp145- or NYVAC-gp145-infected cells
Summary
Since the discovery of the Human Immunodeficiency Virus type 1 (HIV-1) as the causal agent of Acquired Immunodeficiency Syndrome (AIDS) in 1983 [1], many efforts have been performed to discontinue the HIV/AIDS pandemic. The latest estimate indicates that 37.9 million people were living with HIV/AIDS worldwide at the end of 2018 and 770.000 persons died of AIDS in 2018, with sub-Saharan Africa continuing the region most severely affected by the HIV/AIDS pandemic (http:// www.unaids.org/en). A significant success in the HIV field has been the development of the life-saving combined antiretroviral therapy (cART) able to suppress the plasma viremia and reduce the risk of HIV-1 transmission [2] and its accessibility to an increasing number of people worldwide. A safe and effective vaccine able to prevent and eliminate the HIV/AIDS pandemic is mandatory but still missing. The RV144 regimen, novel vaccines based on adenovirus vectors, mosaic immunogens, optimized gp140 proteins (such as HIV-1 Env SOSIP trimers) and passive administration of monoclonal antibodies are among the most recent strategies for HIV-1 prevention and treatment
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