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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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Related in: MedlinePlus

Recombination events between SIVmac239Δnef and SIVsmE660. During the chronic phase of infection or after in vivo CD8 depletion we used bulk sequencing to detect recombination between SIVmac239Δnef and SIVsmE660. Represented are the regions that most closely align to either SIVmac239Δnef (red) or SIVsmE660 (blue). Positioning of putative break points and size of either SIVmac239Δnef or SIVsmE660 regions are approximations based on sequencing data. Open boxes represent regions of the virus where sequences could not be obtained.
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fig7: Recombination events between SIVmac239Δnef and SIVsmE660. During the chronic phase of infection or after in vivo CD8 depletion we used bulk sequencing to detect recombination between SIVmac239Δnef and SIVsmE660. Represented are the regions that most closely align to either SIVmac239Δnef (red) or SIVsmE660 (blue). Positioning of putative break points and size of either SIVmac239Δnef or SIVsmE660 regions are approximations based on sequencing data. Open boxes represent regions of the virus where sequences could not be obtained.

Mentions: One possible explanation for the emergence of SIVmac239-like sequences in these two epitopes was that recombination had occurred between the vaccine and challenge viruses. Indeed, bulk sequencing of the entire viral genome at 8 mo p.c. showed that multiple recombination events had occurred in the two Mamu-B*17+ animals. Further analysis of all of the vaccinated animals revealed recombination occurring in several other animals (Fig. 7). Additionally, sequence analysis of animals 01022 and 01048 confirmed that only SIVmac239Δnef was replicating in these animals. Interestingly, the virus in the two vaccinated Mamu-B*17+ macaques had similar patterns of recombination and replicated to a level ∼1 log higher at 1 yr p.c. than the unvaccinated Mamu-B*17+ animals infected with SIVsmE660 alone (Figs. 6 and 7). This suggests that recombination provided a fitness advantage for replication in Mamu-B*17+ animals.


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)

Recombination events between SIVmac239Δnef and SIVsmE660. During the chronic phase of infection or after in vivo CD8 depletion we used bulk sequencing to detect recombination between SIVmac239Δnef and SIVsmE660. Represented are the regions that most closely align to either SIVmac239Δnef (red) or SIVsmE660 (blue). Positioning of putative break points and size of either SIVmac239Δnef or SIVsmE660 regions are approximations based on sequencing data. Open boxes represent regions of the virus where sequences could not be obtained.
© Copyright Policy
Related In: Results  -  Collection

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

fig7: Recombination events between SIVmac239Δnef and SIVsmE660. During the chronic phase of infection or after in vivo CD8 depletion we used bulk sequencing to detect recombination between SIVmac239Δnef and SIVsmE660. Represented are the regions that most closely align to either SIVmac239Δnef (red) or SIVsmE660 (blue). Positioning of putative break points and size of either SIVmac239Δnef or SIVsmE660 regions are approximations based on sequencing data. Open boxes represent regions of the virus where sequences could not be obtained.
Mentions: One possible explanation for the emergence of SIVmac239-like sequences in these two epitopes was that recombination had occurred between the vaccine and challenge viruses. Indeed, bulk sequencing of the entire viral genome at 8 mo p.c. showed that multiple recombination events had occurred in the two Mamu-B*17+ animals. Further analysis of all of the vaccinated animals revealed recombination occurring in several other animals (Fig. 7). Additionally, sequence analysis of animals 01022 and 01048 confirmed that only SIVmac239Δnef was replicating in these animals. Interestingly, the virus in the two vaccinated Mamu-B*17+ macaques had similar patterns of recombination and replicated to a level ∼1 log higher at 1 yr p.c. than the unvaccinated Mamu-B*17+ animals infected with SIVsmE660 alone (Figs. 6 and 7). This suggests that recombination provided a fitness advantage for replication in Mamu-B*17+ animals.

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