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Vaccination against heterologous R5 clade C SHIV: prevention of infection and correlates of protection.

Lakhashe SK, Wang W, Siddappa NB, Hemashettar G, Polacino P, Hu SL, Villinger F, Else JG, Novembre FJ, Yoon JK, Lee SJ, Montefiori DC, Ruprecht RM, Rasmussen RA - PLoS ONE (2011)

Bottom Line: A safe, efficacious vaccine is required to stop the AIDS pandemic.Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001).These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time.

View Article: PubMed Central - PubMed

Affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.

ABSTRACT
A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time.

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Related in: MedlinePlus

Immune responses on the day of high-dose virus challenge.Cellular and nAb responses at week 0 (day of first virus exposure) and week 7 (day of high-dose virus challenge) for: (A) SIV Gag- and HIV-1 Tat-specific IFN-γ ELISPOT responses. (B) SIV Gag and HIV-1 Tat-specific peripheral blood CD4+ and CD8+ T cells producing intracellular IFN-γ, IL-2 & TNF-α (measured by multiparameter flow cytometry). (C) nAb titers against the challenge virus (IC50 measured by TZM-bl assay).
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pone-0022010-g006: Immune responses on the day of high-dose virus challenge.Cellular and nAb responses at week 0 (day of first virus exposure) and week 7 (day of high-dose virus challenge) for: (A) SIV Gag- and HIV-1 Tat-specific IFN-γ ELISPOT responses. (B) SIV Gag and HIV-1 Tat-specific peripheral blood CD4+ and CD8+ T cells producing intracellular IFN-γ, IL-2 & TNF-α (measured by multiparameter flow cytometry). (C) nAb titers against the challenge virus (IC50 measured by TZM-bl assay).

Mentions: On the day of high-dose rechallenge (week 7), just prior to virus re-exposure, the SHIV-specific cellular responses had significantly declined compared to week 0 values in three out of the four vaccinees (RRi-11, RTr-11, RGe-11) that had remained aviremic after the initial five low-dose virus exposures (Figure 6A, 6B). We ascribe this lack of anamnestic responses to these monkeys remaining uninfected, either because of an insufficient virus dose or immune protection. The fourth monkey, RFo-11, had no detectable cytokine production at either week 0 or 7 and was infected after the single-high dose exposure.


Vaccination against heterologous R5 clade C SHIV: prevention of infection and correlates of protection.

Lakhashe SK, Wang W, Siddappa NB, Hemashettar G, Polacino P, Hu SL, Villinger F, Else JG, Novembre FJ, Yoon JK, Lee SJ, Montefiori DC, Ruprecht RM, Rasmussen RA - PLoS ONE (2011)

Immune responses on the day of high-dose virus challenge.Cellular and nAb responses at week 0 (day of first virus exposure) and week 7 (day of high-dose virus challenge) for: (A) SIV Gag- and HIV-1 Tat-specific IFN-γ ELISPOT responses. (B) SIV Gag and HIV-1 Tat-specific peripheral blood CD4+ and CD8+ T cells producing intracellular IFN-γ, IL-2 & TNF-α (measured by multiparameter flow cytometry). (C) nAb titers against the challenge virus (IC50 measured by TZM-bl assay).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140488&req=5

pone-0022010-g006: Immune responses on the day of high-dose virus challenge.Cellular and nAb responses at week 0 (day of first virus exposure) and week 7 (day of high-dose virus challenge) for: (A) SIV Gag- and HIV-1 Tat-specific IFN-γ ELISPOT responses. (B) SIV Gag and HIV-1 Tat-specific peripheral blood CD4+ and CD8+ T cells producing intracellular IFN-γ, IL-2 & TNF-α (measured by multiparameter flow cytometry). (C) nAb titers against the challenge virus (IC50 measured by TZM-bl assay).
Mentions: On the day of high-dose rechallenge (week 7), just prior to virus re-exposure, the SHIV-specific cellular responses had significantly declined compared to week 0 values in three out of the four vaccinees (RRi-11, RTr-11, RGe-11) that had remained aviremic after the initial five low-dose virus exposures (Figure 6A, 6B). We ascribe this lack of anamnestic responses to these monkeys remaining uninfected, either because of an insufficient virus dose or immune protection. The fourth monkey, RFo-11, had no detectable cytokine production at either week 0 or 7 and was infected after the single-high dose exposure.

Bottom Line: A safe, efficacious vaccine is required to stop the AIDS pandemic.Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001).These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time.

View Article: PubMed Central - PubMed

Affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America.

ABSTRACT
A safe, efficacious vaccine is required to stop the AIDS pandemic. Disappointing results from the STEP trial implied a need to include humoral anti-HIV-1 responses, a notion supported by RV144 trial data even though correlates of protection are unknown. We vaccinated rhesus macaques with recombinant simian immunodeficiency virus (SIV) Gag-Pol particles, HIV-1 Tat and trimeric clade C (HIV-C) gp160, which induced cross-neutralizing antibodies (nAbs) and robust cellular immune responses. After five low-dose mucosal challenges with a simian-human immunodeficiency virus (SHIV) that encoded a heterologous R5 HIV-C envelope (22.1% divergence from the gp160 immunogen), 94% of controls became viremic, whereas one third of vaccinees remained virus-free. Upon high-dose SHIV rechallenge, all controls became infected, whereas some vaccinees remained aviremic. Peak viremia was inversely correlated with both cellular immunity (p<0.001) and cross-nAb titers (p<0.001). These data simultaneously linked cellular as well as humoral immune responses with the degree of protection for the first time.

Show MeSH
Related in: MedlinePlus