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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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Related in: MedlinePlus

Quantitation of viral load upon intravenous virus challenge with SHIV89.6Pcy243 in control and vaccinated monkeys.In the left panels are reported the (A) plasma viremia and (B) the proviral DNA of control macaques. In the right panels are reported the (C) plasma viremia and the (D) proviral DNA of vaccinated macaques. In the bottom panels are indicated the trend line as a LOESS smoothed average of (E) plasma viral RNA and (F) proviral DNA of vaccinated (dashed line) and control (continous line) macaques. Statistical analyses were performed according to the Regression model for correlated data (means with 95% confidence limits).
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pone-0111360-g003: Quantitation of viral load upon intravenous virus challenge with SHIV89.6Pcy243 in control and vaccinated monkeys.In the left panels are reported the (A) plasma viremia and (B) the proviral DNA of control macaques. In the right panels are reported the (C) plasma viremia and the (D) proviral DNA of vaccinated macaques. In the bottom panels are indicated the trend line as a LOESS smoothed average of (E) plasma viral RNA and (F) proviral DNA of vaccinated (dashed line) and control (continous line) macaques. Statistical analyses were performed according to the Regression model for correlated data (means with 95% confidence limits).

Mentions: At week 50, all monkeys were inoculated intravenously with 15 MID50 of the highly pathogenic SHIV89.6Pcy243 grown in cynos [34]. All control animals became viremic with a peak viremia (1×105−1×107 RNA Eq/ml) at week 2 after infection (Fig. 3A). Afterwards, from week 8 to week 74, RNA viral loads in plasma declined although remaining always detectable (range: 6.4×10−1.7×104 RNA Eq/ml), with the exception of monkeys AC921 and AG934 that experienced the lowest peak viremia, which then fell below the threshold limit of detection of the assay (50 RNA Eq/ml). In agreement with this kinetics, the proviral loads peaked two weeks after challenge in all control monkeys and remained detectable (range: 39–20,261 proviral copies/µg DNA) up to week 74, irrespective of the viremia levels (Fig. 3B). Two control monkeys (AC032, AC739) died at weeks 40 and 46 after challenge, respectively.


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)

Quantitation of viral load upon intravenous virus challenge with SHIV89.6Pcy243 in control and vaccinated monkeys.In the left panels are reported the (A) plasma viremia and (B) the proviral DNA of control macaques. In the right panels are reported the (C) plasma viremia and the (D) proviral DNA of vaccinated macaques. In the bottom panels are indicated the trend line as a LOESS smoothed average of (E) plasma viral RNA and (F) proviral DNA of vaccinated (dashed line) and control (continous line) macaques. Statistical analyses were performed according to the Regression model for correlated data (means with 95% confidence limits).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111360-g003: Quantitation of viral load upon intravenous virus challenge with SHIV89.6Pcy243 in control and vaccinated monkeys.In the left panels are reported the (A) plasma viremia and (B) the proviral DNA of control macaques. In the right panels are reported the (C) plasma viremia and the (D) proviral DNA of vaccinated macaques. In the bottom panels are indicated the trend line as a LOESS smoothed average of (E) plasma viral RNA and (F) proviral DNA of vaccinated (dashed line) and control (continous line) macaques. Statistical analyses were performed according to the Regression model for correlated data (means with 95% confidence limits).
Mentions: At week 50, all monkeys were inoculated intravenously with 15 MID50 of the highly pathogenic SHIV89.6Pcy243 grown in cynos [34]. All control animals became viremic with a peak viremia (1×105−1×107 RNA Eq/ml) at week 2 after infection (Fig. 3A). Afterwards, from week 8 to week 74, RNA viral loads in plasma declined although remaining always detectable (range: 6.4×10−1.7×104 RNA Eq/ml), with the exception of monkeys AC921 and AG934 that experienced the lowest peak viremia, which then fell below the threshold limit of detection of the assay (50 RNA Eq/ml). In agreement with this kinetics, the proviral loads peaked two weeks after challenge in all control monkeys and remained detectable (range: 39–20,261 proviral copies/µg DNA) up to week 74, irrespective of the viremia levels (Fig. 3B). Two control monkeys (AC032, AC739) died at weeks 40 and 46 after challenge, respectively.

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