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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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Plasma viral RNA (vRNA) loads after SHIV-1157ipEL-p challenges and Kaplan-Meier plots.(A–D) vRNA loads after low-dose viral challenges for Groups 1-4. Black symbols, vRNA loads of Groups 1-4 during the weekly low-dose challenges (blue arrows); red symbols, vRNA loads of animals later given high-dose challenge (red arrows; see also Figure 1 legend). (E) Kaplan-Meier plots depicting the fraction of monkeys remaining aviremic. (F) Kaplan-Meier plots depicting the fraction of animals not yet having reached peak viremia. (G–H) vRNA loads after a single high-dose SHIV-1157ipEL-p challenge of newly recruited naïve controls (Group 5) plus prior control monkey RAk-11 (G), or rechallenge of vaccinees (H). Probability (P) values were determined by 2-sided log-rank analysis. Horizontal dashed lines in A–D, G–H: limit of RT-PCR assay detection (50 vRNA copies/ml; [25]).
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pone-0022010-g004: Plasma viral RNA (vRNA) loads after SHIV-1157ipEL-p challenges and Kaplan-Meier plots.(A–D) vRNA loads after low-dose viral challenges for Groups 1-4. Black symbols, vRNA loads of Groups 1-4 during the weekly low-dose challenges (blue arrows); red symbols, vRNA loads of animals later given high-dose challenge (red arrows; see also Figure 1 legend). (E) Kaplan-Meier plots depicting the fraction of monkeys remaining aviremic. (F) Kaplan-Meier plots depicting the fraction of animals not yet having reached peak viremia. (G–H) vRNA loads after a single high-dose SHIV-1157ipEL-p challenge of newly recruited naïve controls (Group 5) plus prior control monkey RAk-11 (G), or rechallenge of vaccinees (H). Probability (P) values were determined by 2-sided log-rank analysis. Horizontal dashed lines in A–D, G–H: limit of RT-PCR assay detection (50 vRNA copies/ml; [25]).

Mentions: All vaccinated (Groups 1 and 2) and control RM (Group 3 plus Group 4, as a part of another study) were given five i.r. low-dose SHIV-1157ipEL-p challenges (8000 50% tissue culture infectious doses (TCID50) measured by TZM-bl assay) (Figure 1). Env of the challenge virus was heterologous to the HIV1084i gp160 immunogen (22.1% divergent) (Figure 1B), whereas the challenge virus Gag was partially heterologous to the Gag-Pol particles given to Group 1 (Figure S1). Three weeks after the final low-dose virus exposure, 94% of all controls (Groups 3+4) were infected, compared to 67% of all vaccinees (P = 0.07 by Fisher's exact test (one-sided)); monkeys RFo-11, RGe-11, RRi-11 and RTr-11 remained aviremic (Figure 4A–D). The vaccinees' mean peak plasma viral RNA (vRNA) load was significantly lower than the combined controls' (6.6×105 versus 2.8×106 copies/ml; P = 0.045, Wilcoxon rank-sum test (for statistical analysis, aviremic RM were assigned a vRNA load of 49 copies/ml, based upon an assay sensitivity of 50 copies/ml [25]). Likewise, the mean 7-week “area under the curve” viral loads differed significantly between the vaccinees and controls (P = 0.01). The combined vaccinees of Groups 1+2 also had significant delays in both time until first detectable viremia (Figure 4E) and time until peak viremia (Figure 4F) compared to the combined Groups 3+4 controls. Significant delays of both parameters were also observed when Group 1+2 vaccinees were compared only to Group 3 controls (Figure S2).


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)

Plasma viral RNA (vRNA) loads after SHIV-1157ipEL-p challenges and Kaplan-Meier plots.(A–D) vRNA loads after low-dose viral challenges for Groups 1-4. Black symbols, vRNA loads of Groups 1-4 during the weekly low-dose challenges (blue arrows); red symbols, vRNA loads of animals later given high-dose challenge (red arrows; see also Figure 1 legend). (E) Kaplan-Meier plots depicting the fraction of monkeys remaining aviremic. (F) Kaplan-Meier plots depicting the fraction of animals not yet having reached peak viremia. (G–H) vRNA loads after a single high-dose SHIV-1157ipEL-p challenge of newly recruited naïve controls (Group 5) plus prior control monkey RAk-11 (G), or rechallenge of vaccinees (H). Probability (P) values were determined by 2-sided log-rank analysis. Horizontal dashed lines in A–D, G–H: limit of RT-PCR assay detection (50 vRNA copies/ml; [25]).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3140488&req=5

pone-0022010-g004: Plasma viral RNA (vRNA) loads after SHIV-1157ipEL-p challenges and Kaplan-Meier plots.(A–D) vRNA loads after low-dose viral challenges for Groups 1-4. Black symbols, vRNA loads of Groups 1-4 during the weekly low-dose challenges (blue arrows); red symbols, vRNA loads of animals later given high-dose challenge (red arrows; see also Figure 1 legend). (E) Kaplan-Meier plots depicting the fraction of monkeys remaining aviremic. (F) Kaplan-Meier plots depicting the fraction of animals not yet having reached peak viremia. (G–H) vRNA loads after a single high-dose SHIV-1157ipEL-p challenge of newly recruited naïve controls (Group 5) plus prior control monkey RAk-11 (G), or rechallenge of vaccinees (H). Probability (P) values were determined by 2-sided log-rank analysis. Horizontal dashed lines in A–D, G–H: limit of RT-PCR assay detection (50 vRNA copies/ml; [25]).
Mentions: All vaccinated (Groups 1 and 2) and control RM (Group 3 plus Group 4, as a part of another study) were given five i.r. low-dose SHIV-1157ipEL-p challenges (8000 50% tissue culture infectious doses (TCID50) measured by TZM-bl assay) (Figure 1). Env of the challenge virus was heterologous to the HIV1084i gp160 immunogen (22.1% divergent) (Figure 1B), whereas the challenge virus Gag was partially heterologous to the Gag-Pol particles given to Group 1 (Figure S1). Three weeks after the final low-dose virus exposure, 94% of all controls (Groups 3+4) were infected, compared to 67% of all vaccinees (P = 0.07 by Fisher's exact test (one-sided)); monkeys RFo-11, RGe-11, RRi-11 and RTr-11 remained aviremic (Figure 4A–D). The vaccinees' mean peak plasma viral RNA (vRNA) load was significantly lower than the combined controls' (6.6×105 versus 2.8×106 copies/ml; P = 0.045, Wilcoxon rank-sum test (for statistical analysis, aviremic RM were assigned a vRNA load of 49 copies/ml, based upon an assay sensitivity of 50 copies/ml [25]). Likewise, the mean 7-week “area under the curve” viral loads differed significantly between the vaccinees and controls (P = 0.01). The combined vaccinees of Groups 1+2 also had significant delays in both time until first detectable viremia (Figure 4E) and time until peak viremia (Figure 4F) compared to the combined Groups 3+4 controls. Significant delays of both parameters were also observed when Group 1+2 vaccinees were compared only to Group 3 controls (Figure S2).

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