Nonhuman Primate Reagent Resource, MassBiologics
Amino Acids, Peptides, and Proteins | Immunity | Immunology of Infectious Disease | Immunoprophylaxis and Therapy | Virology | Virus Diseases | Viruses
Generating durable humoral immunity through vaccination depends upon effective interaction of follicular helper T cells (Tfh) with germinal center (GC) B cells. Th1 polarization of Tfh cells is an important process shaping the success of Tfh-GC B cell interactions by influencing co-stimulatory and cytokine-dependent Tfh help to B cells. However, the question remains whether adjuvant-dependent modulation of Tfh cells enhances HIV-1 vaccine-induced anti-Envelope (Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of Th1-polarized Tfh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferon-induced protein (IP)-10-adjuvanted HIV-1 DNA prime, followed by an MPLA+QS-21-adjuvanted Env protein boost in macaques (DIP-10 PALFQ), we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity to V1V2, and effector functions when compared to macaques primed with DNA lacking IP-10 and boosted with MPLA+alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibodies in serum, showing for the first time that adjuvants can dramatically impact the IgG subclass profile in macaques. The DIP-10 PALFQ regimen also increased vaginal and rectal IgA antibodies to a greater extent. Within lymph nodes, we observed augmented GC B cell responses and promotion of Th1 gene expression profiles in GC Tfh cells. The frequency of GC Tfh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of Th1-Tfh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody response.
IMPORTANCE The results of the RV144 trial demonstrated that vaccination could prevent HIV transmission in humans and that longevity of anti-Env antibodies may be key to this protection. Efforts to improve upon the prime-boost vaccine regimen used in RV144 have indicated that booster immunizations increase serum anti-Env antibody titers but only transiently. Poor antibody durability hampers efforts to develop an effective HIV-1 vaccine. This study was designed to identify the specific elements involved in the immunological mechanism necessary to produce robust HIV-1 specific antibodies in rhesus macaques. By clearly defining immune-mediated pathways that improve the magnitude and functionality of the anti-HIV-1 antibody response, we will have the foundation necessary for rational development of an HIV-1 vaccine.
HIV-1 vaccine, antibody responses
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Copyright © 2019 Verma et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
DOI of Published Version
J Virol. 2019 Dec 11. pii: JVI.01737-19. doi: 10.1128/JVI.01737-19. [Epub ahead of print] Link to article on publisher's site
Journal of virology
Verma A, Reimann KA, Foehl DH, Iyer SS. (2019). Impact of Th1 CD4 TFH skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques. Open Access Articles. https://doi.org/10.1128/JVI.01737-19. Retrieved from https://escholarship.umassmed.edu/oapubs/4096
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This work is licensed under a Creative Commons Attribution 4.0 License.
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