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Macaques vaccinated with live-attenuated SIV control replication of heterologous virus.

Reynolds MR, Weiler AM, Weisgrau KL, Piaskowski SM, Furlott JR, Weinfurter JT, Kaizu M, Soma T, León EJ, MacNair C, Leaman DP, Zwick MB, Gostick E, Musani SK, Price DA, Friedrich TC, Rakasz EG, Wilson NA, McDermott AB, Boyle R, Allison DB, Burton DR, Koff WC, Watkins DI - J. Exp. Med. (2008)

Bottom Line: An effective AIDS vaccine will need to protect against globally diverse isolates of HIV.Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge.On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.

View Article: PubMed Central - PubMed

Affiliation: AIDS Vaccine Research Laboratory, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA. mrreynol@wisc.edu

ABSTRACT
An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8(+) T cells in this control. Furthermore, transient depletion of peripheral CD8(+) lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.

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Plasma virus concentrations and CD8+ T cell and NK cell counts after in vivo depletion of CD8+ cells. (a) Plasma virus concentrations of the four SIVmac239Δnef-vaccinated macaques were transiently depleted of their peripheral CD8+ cells. (b and c) The number of CD8+ T cells (CD3+/CD8+ lymphocytes; b) and the number of NK cells (CD3−/CD8+/CD16+; c) in the PBMC after in vivo CD8 depletion.
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fig5: Plasma virus concentrations and CD8+ T cell and NK cell counts after in vivo depletion of CD8+ cells. (a) Plasma virus concentrations of the four SIVmac239Δnef-vaccinated macaques were transiently depleted of their peripheral CD8+ cells. (b and c) The number of CD8+ T cells (CD3+/CD8+ lymphocytes; b) and the number of NK cells (CD3−/CD8+/CD16+; c) in the PBMC after in vivo CD8 depletion.

Mentions: Because neutralizing antibodies did not appear to be responsible for control of viral replication, we next investigated whether CD8+ cells were important in vaccine-mediated control of replication. Therefore, we depleted CD8+ cells in vivo at 11 mo p.c. in the four SIVmac239Δnef-vaccinated animals controlling virus replication below 5,000 vRNA copy Eq/ml plasma. We administered a monoclonal antibody specific for CD8α to transiently deplete CD8+ cells, which includes both CD8+ T cells and NK cells, from the periphery. 1 d after administering the antibody, CD8+ T cells were almost completely absent from the PBMC in three of the animals and reduced by >50% in the fourth. During the period of CD8+ cell depletion, plasma virus concentrations increased by 1–3 logs (Fig. 5 a). Plasma virus replication peaked 7–10 d after in vivo depletion of CD8+ cells and ranged between 2.3 × 104 and 5.5 × 105 vRNA copy Eq/ml. CD8+ cells reemerged in the periphery 17–28 d after depletion, concomitant with a decrease in plasma virus concentrations (Fig. 5, b and c). Only animal 01048, however, controlled virus replication at or below predepletion levels by 5 mo after CD8+ cell depletion. Conversely, animal 02132 never regained control of virus replication below 5,000 vRNA Eq/ml.


Macaques vaccinated with live-attenuated SIV control replication of heterologous virus.

Reynolds MR, Weiler AM, Weisgrau KL, Piaskowski SM, Furlott JR, Weinfurter JT, Kaizu M, Soma T, León EJ, MacNair C, Leaman DP, Zwick MB, Gostick E, Musani SK, Price DA, Friedrich TC, Rakasz EG, Wilson NA, McDermott AB, Boyle R, Allison DB, Burton DR, Koff WC, Watkins DI - J. Exp. Med. (2008)

Plasma virus concentrations and CD8+ T cell and NK cell counts after in vivo depletion of CD8+ cells. (a) Plasma virus concentrations of the four SIVmac239Δnef-vaccinated macaques were transiently depleted of their peripheral CD8+ cells. (b and c) The number of CD8+ T cells (CD3+/CD8+ lymphocytes; b) and the number of NK cells (CD3−/CD8+/CD16+; c) in the PBMC after in vivo CD8 depletion.
© Copyright Policy
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2571929&req=5

fig5: Plasma virus concentrations and CD8+ T cell and NK cell counts after in vivo depletion of CD8+ cells. (a) Plasma virus concentrations of the four SIVmac239Δnef-vaccinated macaques were transiently depleted of their peripheral CD8+ cells. (b and c) The number of CD8+ T cells (CD3+/CD8+ lymphocytes; b) and the number of NK cells (CD3−/CD8+/CD16+; c) in the PBMC after in vivo CD8 depletion.
Mentions: Because neutralizing antibodies did not appear to be responsible for control of viral replication, we next investigated whether CD8+ cells were important in vaccine-mediated control of replication. Therefore, we depleted CD8+ cells in vivo at 11 mo p.c. in the four SIVmac239Δnef-vaccinated animals controlling virus replication below 5,000 vRNA copy Eq/ml plasma. We administered a monoclonal antibody specific for CD8α to transiently deplete CD8+ cells, which includes both CD8+ T cells and NK cells, from the periphery. 1 d after administering the antibody, CD8+ T cells were almost completely absent from the PBMC in three of the animals and reduced by >50% in the fourth. During the period of CD8+ cell depletion, plasma virus concentrations increased by 1–3 logs (Fig. 5 a). Plasma virus replication peaked 7–10 d after in vivo depletion of CD8+ cells and ranged between 2.3 × 104 and 5.5 × 105 vRNA copy Eq/ml. CD8+ cells reemerged in the periphery 17–28 d after depletion, concomitant with a decrease in plasma virus concentrations (Fig. 5, b and c). Only animal 01048, however, controlled virus replication at or below predepletion levels by 5 mo after CD8+ cell depletion. Conversely, animal 02132 never regained control of virus replication below 5,000 vRNA Eq/ml.

Bottom Line: An effective AIDS vaccine will need to protect against globally diverse isolates of HIV.Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge.On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.

View Article: PubMed Central - PubMed

Affiliation: AIDS Vaccine Research Laboratory, Wisconsin National Primate Research Center, University of Wisconsin-Madison, Madison, WI 53715, USA. mrreynol@wisc.edu

ABSTRACT
An effective AIDS vaccine will need to protect against globally diverse isolates of HIV. To address this issue in macaques, we administered a live-attenuated simian immunodeficiency virus (SIV) vaccine and challenged with a highly pathogenic heterologous isolate. Vaccinees reduced viral replication by approximately 2 logs between weeks 2-32 (P < or = 0.049) postchallenge. Remarkably, vaccinees expressing MHC-I (MHC class I) alleles previously associated with viral control completely suppressed acute phase replication of the challenge virus, implicating CD8(+) T cells in this control. Furthermore, transient depletion of peripheral CD8(+) lymphocytes in four vaccinees during the chronic phase resulted in an increase in virus replication. In two of these animals, the recrudescent virus population contained only the vaccine strain and not the challenge virus. Alarmingly, however, we found evidence of recombinant viruses emerging in some of the vaccinated animals. This finding argues strongly against an attenuated virus vaccine as a solution to the AIDS epidemic. On a more positive note, our results suggest that MHC-I-restricted CD8(+) T cells contribute to the protection induced by the live-attenuated SIV vaccine and demonstrate that vaccine-induced CD8(+) T cell responses can control replication of heterologous challenge viruses.

Show MeSH
Related in: MedlinePlus