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Biocompatible anionic polymeric microspheres as priming delivery system for effetive HIV/AIDS Tat-based vaccines.

Titti F, Maggiorella MT, Ferrantelli F, Sernicola L, Bellino S, Collacchi B, Fanales Belasio E, Moretti S, Pavone Cossut MR, Belli R, Olivieri E, Farcomeni S, Compagnoni D, Michelini Z, Sabbatucci M, Sparnacci K, Tondelli L, Laus M, Cafaro A, Caputo A, Ensoli B - PLoS ONE (2014)

Bottom Line: Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat.Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity.Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.

ABSTRACT
Here we describe a prime-boost regimen of vaccination in Macaca fascicularis that combines priming with novel anionic microspheres designed to deliver the biologically active HIV-1 Tat protein and boosting with Tat in Alum. This regimen of immunization modulated the IgG subclass profile and elicited a balanced Th1-Th2 type of humoral and cellular responses. Remarkably, following intravenous challenge with SHIV89.6Pcy243, vaccinees significantly blunted acute viremia, as compared to control monkeys, and this control was associated with significantly lower CD4+ T cell depletion rate during the acute phase of infection and higher ability to resume the CD4+ T cell counts in the post-acute and chronic phases of infection. The long lasting control of viremia was associated with the persistence of high titers anti-Tat antibodies whose profile clearly distinguished vaccinees in controllers and viremics. Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat. Finally, among vaccinees, titers of anti-Tat IgG1, IgG3 and IgG4 subclasses had a significant association with control of viremia in the acute and post-acute phases of infection. Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity. Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

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Anti-Tat IgG subclass profile before challenge and virological outcome.(A) The box-blot analysis represents the anti-Tat IgG and IgG subclass profile in plasma of cynomolgus macaques before (week 23) and after (week 44) the last Tat/Alum boost. For the anti-Tat IgG subclass profile, a cut off for each subclass was established based on the analyses of IgG subclasses in plasma of 30 naive cynomolgus macaques, as described in material and methods. (B) The rate of plasma viral load decline among vaccinees is indicated where the lines (dashed red lines for viremic; continous black lines for controllers) represent the mobile median starting from the first positive viremia sample during the acute phase of the infection. (C) The impact of anti-Tat IgG1 titers on the rate of vRNA decline during the post acute phase of the infection, as determined at week 44 during the immunization, is reported.
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pone-0111360-g007: Anti-Tat IgG subclass profile before challenge and virological outcome.(A) The box-blot analysis represents the anti-Tat IgG and IgG subclass profile in plasma of cynomolgus macaques before (week 23) and after (week 44) the last Tat/Alum boost. For the anti-Tat IgG subclass profile, a cut off for each subclass was established based on the analyses of IgG subclasses in plasma of 30 naive cynomolgus macaques, as described in material and methods. (B) The rate of plasma viral load decline among vaccinees is indicated where the lines (dashed red lines for viremic; continous black lines for controllers) represent the mobile median starting from the first positive viremia sample during the acute phase of the infection. (C) The impact of anti-Tat IgG1 titers on the rate of vRNA decline during the post acute phase of the infection, as determined at week 44 during the immunization, is reported.

Mentions: We next determined whether the profile of anti-Tat IgG subclasses induced by vaccination had a potential association with pre-challenge T-cell responses or could serve as a predictor of vaccine efficacy. Thus, anti-Tat IgG subclasses were evaluated at weeks 21 (3 weeks after the last Tat/H1D immunization) and 44 (7 weeks after the second Tat/Alum boost). It was immediately apparent that the Tat/Alum boost had markedly modulated the IgG subclass profile. In fact, after the Tat/Alum boost the IgG1 became the most represented isotype, followed by IgG2, and then by IgG3 and IgG4, which displayed comparable titers (Fig. 7A; Table S2). Thus, as already observed for T cell responses, the Tat/H1D/Alum vaccine elicited a balanced Th1/Th2 type of humoral responses.


Biocompatible anionic polymeric microspheres as priming delivery system for effetive HIV/AIDS Tat-based vaccines.

Titti F, Maggiorella MT, Ferrantelli F, Sernicola L, Bellino S, Collacchi B, Fanales Belasio E, Moretti S, Pavone Cossut MR, Belli R, Olivieri E, Farcomeni S, Compagnoni D, Michelini Z, Sabbatucci M, Sparnacci K, Tondelli L, Laus M, Cafaro A, Caputo A, Ensoli B - PLoS ONE (2014)

Anti-Tat IgG subclass profile before challenge and virological outcome.(A) The box-blot analysis represents the anti-Tat IgG and IgG subclass profile in plasma of cynomolgus macaques before (week 23) and after (week 44) the last Tat/Alum boost. For the anti-Tat IgG subclass profile, a cut off for each subclass was established based on the analyses of IgG subclasses in plasma of 30 naive cynomolgus macaques, as described in material and methods. (B) The rate of plasma viral load decline among vaccinees is indicated where the lines (dashed red lines for viremic; continous black lines for controllers) represent the mobile median starting from the first positive viremia sample during the acute phase of the infection. (C) The impact of anti-Tat IgG1 titers on the rate of vRNA decline during the post acute phase of the infection, as determined at week 44 during the immunization, is reported.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4214729&req=5

pone-0111360-g007: Anti-Tat IgG subclass profile before challenge and virological outcome.(A) The box-blot analysis represents the anti-Tat IgG and IgG subclass profile in plasma of cynomolgus macaques before (week 23) and after (week 44) the last Tat/Alum boost. For the anti-Tat IgG subclass profile, a cut off for each subclass was established based on the analyses of IgG subclasses in plasma of 30 naive cynomolgus macaques, as described in material and methods. (B) The rate of plasma viral load decline among vaccinees is indicated where the lines (dashed red lines for viremic; continous black lines for controllers) represent the mobile median starting from the first positive viremia sample during the acute phase of the infection. (C) The impact of anti-Tat IgG1 titers on the rate of vRNA decline during the post acute phase of the infection, as determined at week 44 during the immunization, is reported.
Mentions: We next determined whether the profile of anti-Tat IgG subclasses induced by vaccination had a potential association with pre-challenge T-cell responses or could serve as a predictor of vaccine efficacy. Thus, anti-Tat IgG subclasses were evaluated at weeks 21 (3 weeks after the last Tat/H1D immunization) and 44 (7 weeks after the second Tat/Alum boost). It was immediately apparent that the Tat/Alum boost had markedly modulated the IgG subclass profile. In fact, after the Tat/Alum boost the IgG1 became the most represented isotype, followed by IgG2, and then by IgG3 and IgG4, which displayed comparable titers (Fig. 7A; Table S2). Thus, as already observed for T cell responses, the Tat/H1D/Alum vaccine elicited a balanced Th1/Th2 type of humoral responses.

Bottom Line: Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat.Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity.Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

View Article: PubMed Central - PubMed

Affiliation: National AIDS Center, Istituto Superiore di Sanità, Rome, Italy.

ABSTRACT
Here we describe a prime-boost regimen of vaccination in Macaca fascicularis that combines priming with novel anionic microspheres designed to deliver the biologically active HIV-1 Tat protein and boosting with Tat in Alum. This regimen of immunization modulated the IgG subclass profile and elicited a balanced Th1-Th2 type of humoral and cellular responses. Remarkably, following intravenous challenge with SHIV89.6Pcy243, vaccinees significantly blunted acute viremia, as compared to control monkeys, and this control was associated with significantly lower CD4+ T cell depletion rate during the acute phase of infection and higher ability to resume the CD4+ T cell counts in the post-acute and chronic phases of infection. The long lasting control of viremia was associated with the persistence of high titers anti-Tat antibodies whose profile clearly distinguished vaccinees in controllers and viremics. Controllers, as opposed to vaccinated and viremic cynos, exhibited significantly higher pre-challenge antibody responses to peptides spanning the glutamine-rich and the RGD-integrin-binding regions of Tat. Finally, among vaccinees, titers of anti-Tat IgG1, IgG3 and IgG4 subclasses had a significant association with control of viremia in the acute and post-acute phases of infection. Altogether these findings indicate that the Tat/H1D/Alum regimen of immunization holds promise for next generation vaccines with Tat protein or other proteins for which maintenance of the native conformation and activity are critical for optimal immunogenicity. Our results also provide novel information on the role of anti-Tat responses in the prevention of HIV pathogenesis and for the design of new vaccine candidates.

Show MeSH
Related in: MedlinePlus