Impact of T(h)1 CD4 Follicular Helper T Cell Skewing on Antibody Responses to an HIV-1 Vaccine in Rhesus Macaques

Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (T-fh) cells with germinal center (GC) B cells. T(h)1 polarization of T-fh cells is an important process shaping the success of T-fh-GC B cell interactions by influencing costimulatory...

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Veröffentlicht in:Journal of virology 2020-03, Vol.94 (6), Article 01737
Hauptverfasser: Verma, Anil, Schmidt, Brian A., Elizaldi, Sonny R., Nguyen, Nancy K., Walter, Korey A., Beck, Zoltan, Trinh, Hung, Dinasarapu, Ashok R., Lakshmanappa, Yashavanth Shaan, Rane, Niharika N., Matyas, Gary R., Rao, Mangala, Shen, Xiaoying, Tomaras, Georgia D., LaBranche, Celia C., Reimann, Keith A., Foehl, David H., Gach, Johannes S., Forthal, Donald N., Kozlowski, Pamela A., Amara, Rama R., Iyer, Smita S.
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Sprache:eng
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Zusammenfassung:Generating durable humoral immunity through vaccination depends upon effective interactions of follicular helper T (T-fh) cells with germinal center (GC) B cells. T(h)1 polarization of T-fh cells is an important process shaping the success of T-fh-GC B cell interactions by influencing costimulatory and cytokine-dependent Tfh help to B cells. However, the question remains as to whether adjuvant-dependent modulation of T-fh cells enhances HIV-1 vaccine-induced antienvelope (anti-Env) antibody responses. We investigated whether an HIV-1 vaccine platform designed to increase the number of T(h)1-polarized T-fh cells enhances the magnitude and quality of anti-Env antibodies. Utilizing a novel interferoninduced protein 10 (IP-10)-adjuvanted HIV-1 DNA prime followed by a monophosphoryl lipid A and QS-21 (MPLA+QS-21)-adjuvanted Env protein boost (DIP-10 P-ALFQ) in macaques, we observed higher anti-Env serum IgG titers with greater cross-clade reactivity, specificity for V1V2, and effector functions than in macaques primed with DNA lacking IP-10 and boosted with MPLA-plus-alum-adjuvanted Env protein (DPALFA) The DIP-10 PALFQ vaccine regimen elicited higher anti-Env IgG1 and lower IgG4 antibody levels 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 the promotion of T(h)1 gene expression profiles in GC T-fh cells. The frequency of GC T-fh cells correlated with both the magnitude and avidity of anti-Env serum IgG. Together, these data suggest that adjuvant-induced stimulation of T(h)1-T-fh cells is an effective strategy for enhancing the magnitude and quality of anti-Env antibody responses. 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 can 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 im
ISSN:0022-538X
1098-5514
DOI:10.1128/JVI.01737-19