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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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Antibody responses against HIV-1 Env and Tat proteins after challenge with SHIV89.6Pcy243.Anti-Env IgG antibody titers were determined in plasma of control (A) and vaccinated (B) macaques. In the middle panels are reported the anti-Tat IgG antibody titers in (C) controls and (D) vaccinees. In the bottom panels the anti-Tat IgM antibody titers in (E) controls and (F) vaccinees are indicated. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).
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pone-0111360-g005: Antibody responses against HIV-1 Env and Tat proteins after challenge with SHIV89.6Pcy243.Anti-Env IgG antibody titers were determined in plasma of control (A) and vaccinated (B) macaques. In the middle panels are reported the anti-Tat IgG antibody titers in (C) controls and (D) vaccinees. In the bottom panels the anti-Tat IgM antibody titers in (E) controls and (F) vaccinees are indicated. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).

Mentions: Upon challenge, all control monkeys seroconverted, and anti-Env IgG antibody titers increased reaching a plateau in the chronic phase of infection (Fig. 5A). Similarly, all but one vaccinated monkey (AH776) seroconverted by week 8 (Fig. 5B), and 5 of them (AF134, AG291, AH484, MF770, BD765B) showed increased anti-Env IgG antibody titers afterwards, reaching levels comparable to those observed in the controls. Interestingly, monkey AH776, which exhibited undetectable levels of plasma viremia and proviral load, clearly seroconverted by week 16, showing thereafter lower titers of anti-Env antibodies as compared to the other vaccinees. Among the control macaques, anti-Tat IgG (Fig. 5C) and IgM (Fig. 5D) antibodies were never detectable after challenge. As already observed for T cell responses, vaccinees did not exhibit anti-Tat IgG (Fig. 5E) and IgM (Fig. 5F) anamnestic responses. In particular, anti-Tat IgM antibodies declined soon after challenge, becoming either undetectable or barely detectable in a few monkeys (titer ≤1∶50).


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)

Antibody responses against HIV-1 Env and Tat proteins after challenge with SHIV89.6Pcy243.Anti-Env IgG antibody titers were determined in plasma of control (A) and vaccinated (B) macaques. In the middle panels are reported the anti-Tat IgG antibody titers in (C) controls and (D) vaccinees. In the bottom panels the anti-Tat IgM antibody titers in (E) controls and (F) vaccinees are indicated. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0111360-g005: Antibody responses against HIV-1 Env and Tat proteins after challenge with SHIV89.6Pcy243.Anti-Env IgG antibody titers were determined in plasma of control (A) and vaccinated (B) macaques. In the middle panels are reported the anti-Tat IgG antibody titers in (C) controls and (D) vaccinees. In the bottom panels the anti-Tat IgM antibody titers in (E) controls and (F) vaccinees are indicated. The dashed lines indicate the cut-off values (samples showing titers <1∶25 for IgM and <1∶100 for IgG were scored as negative).
Mentions: Upon challenge, all control monkeys seroconverted, and anti-Env IgG antibody titers increased reaching a plateau in the chronic phase of infection (Fig. 5A). Similarly, all but one vaccinated monkey (AH776) seroconverted by week 8 (Fig. 5B), and 5 of them (AF134, AG291, AH484, MF770, BD765B) showed increased anti-Env IgG antibody titers afterwards, reaching levels comparable to those observed in the controls. Interestingly, monkey AH776, which exhibited undetectable levels of plasma viremia and proviral load, clearly seroconverted by week 16, showing thereafter lower titers of anti-Env antibodies as compared to the other vaccinees. Among the control macaques, anti-Tat IgG (Fig. 5C) and IgM (Fig. 5D) antibodies were never detectable after challenge. As already observed for T cell responses, vaccinees did not exhibit anti-Tat IgG (Fig. 5E) and IgM (Fig. 5F) anamnestic responses. In particular, anti-Tat IgM antibodies declined soon after challenge, becoming either undetectable or barely detectable in a few monkeys (titer ≤1∶50).

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