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Superiority in Rhesus Macaques of Targeting HIV-1 Env Gp140 to CD40 Versus LOX-1 in Combination with Replication Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses.

Superiority in Rhesus Macaques of Targeting HIV-1 Env Gp140 to CD40 Versus LOX-1 in Combination with Replication Competent NYVAC-KC for Induction of Env-Specific Antibody and T Cell Responses.
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Zurawski G, Shen X, Zurawski S, Tomaras GD, Montefiori DC, Roederer M, Ferrari G, Lacabaratz C, Klucar P, Wang Z, Foulds KE, Kao SF, Yu X, Sato A, Yates NL, LaBranche C, Stanfield-Oakley S, Kibler K, Jacobs B, Salazar A, Self S, Fulp J, Gottardo R, Galmin L, Weiss D, Cristillo A, Pantaleo G, Levy Y,


Zurawski G, Shen X, Zurawski S, Tomaras GD, Montefiori DC, Roederer M, Ferrari G, Lacabaratz C, Klucar P, Wang Z, Foulds KE, Kao SF, Yu X, Sato A, Yates NL, LaBranche C, Stanfield-Oakley S, Kibler K, Jacobs B, Salazar A, Self S, Fulp J, Gottardo R, Galmin L, Weiss D, Cristillo A, Pantaleo G, Levy Y, (click to view)

Zurawski G, Shen X, Zurawski S, Tomaras GD, Montefiori DC, Roederer M, Ferrari G, Lacabaratz C, Klucar P, Wang Z, Foulds KE, Kao SF, Yu X, Sato A, Yates NL, LaBranche C, Stanfield-Oakley S, Kibler K, Jacobs B, Salazar A, Self S, Fulp J, Gottardo R, Galmin L, Weiss D, Cristillo A, Pantaleo G, Levy Y,

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Journal of virology 2017 02 15() pii 10.1128/JVI.01596-16

Abstract

We compared the HIV-1-specific immune responses generated by targeting HIV-1 envelope protein (Env gp140) to either CD40 or LOX-1, two endocytic receptors on dendritic cells (DCs), in Rhesus macaques primed with a poxvirus vector (NYVAC-KC) expressing Env gp140. The DC-targeting vaccines, humanized recombinant monoclonal antibodies fused to Env gp140, were administered as a boost with poly ICLC adjuvant either alone or co-administered with the NYVAC-KC vector. All the DC-targeting vaccine administrations with poly ICLC increased the low-level serum anti-Env IgG responses elicited by NYVAC-KC priming significantly more (up to P =0.01) than a group without poly ICLC. The responses were robust, cross-reactive, and contained antibodies specific to multiple epitopes within gp140 including the C1, C2, V1-3, C4, C5, and gp41 immuno-dominant regions. The DC-targeting vaccines also elicited modest serum Env-specific IgA responses. All groups gave serum neutralization activity limited to Tier 1 viruses and antibody dependent cytotoxicity responses (ADCC) after DC-targeting boosts. Furthermore, CD4(+) and CD8(+) T cell responses specific to multiple Env epitopes were strongly boosted by the DC-targeting vaccines + poly ICLC. Together, these results indicate that prime/boost immunization via NYVAC-KC and either αCD40.Env gp140/poly ICLC or αLOX-1.Env gp140/poly ICLC induced balanced antibody and T cell responses against HIV-1 Env. Co-administration of NYVAC-KC with the DC-targeting vaccines increased T cell responses, but had minimal effects on antibody responses except for suppressing serum IgA responses. Overall, compared to LOX-1, targeting Env to CD40 gave more robust T cell and serum antibody responses with broader epitope representation and greater durability.IMPORTANCE An effective vaccine to prevent HIV-1 infection does not yet exist. An approach to elicit strong protective antibody development is to direct virus protein antigens specifically to dendritic cells, which are now known to be the key cell type for controlling immunity. Here we have tested in non-human primates two prototype vaccines engineered to direct the HIV-1 coat protein Env to dendritic cells. These vaccines bind to either CD40 or LOX-1, two dendritic cell surface receptors with different functions and tissue distributions. We tested the vaccines described above in combination with attenuated virus vectors that express Env. Both vaccines, but especially that delivered via CD40, raised robust immunity against HIV-1 as measured by monitoring potentially protective antibody and T cell responses in the blood. The safety and efficacy of the CD40-targeted vaccine justifies further development for future human clinical trials.

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