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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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Frequency of tetramer binding cells in the PBMC of SIVmac239Δnef-vaccinated macaques p.c. with SIVsmE660. (a) The frequency of MHC-I tetramer binding cells in the PBMC after challenge with SIVsmE660. Frequencies of tetramer positive cells are reported as the percentage of CD3+/CD8+/tetramer+ lymphocytes. The plasma virus concentrations for each animal are displayed with the red line and symbols. * distinguishes Nef221-229YY9 from Nef159-167YY9. (b) Comparison of amino acid sequences between SIVmac239-derived peptides and SIVsmE660. The SIVmac239 sequence is shown above SIVsmE660 sequence for comparison of the two viruses. Periods represent conserved amino acids, capital letters indicate amino acid substitutions, and lowercase letters represent mixed populations.
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fig4: Frequency of tetramer binding cells in the PBMC of SIVmac239Δnef-vaccinated macaques p.c. with SIVsmE660. (a) The frequency of MHC-I tetramer binding cells in the PBMC after challenge with SIVsmE660. Frequencies of tetramer positive cells are reported as the percentage of CD3+/CD8+/tetramer+ lymphocytes. The plasma virus concentrations for each animal are displayed with the red line and symbols. * distinguishes Nef221-229YY9 from Nef159-167YY9. (b) Comparison of amino acid sequences between SIVmac239-derived peptides and SIVsmE660. The SIVmac239 sequence is shown above SIVsmE660 sequence for comparison of the two viruses. Periods represent conserved amino acids, capital letters indicate amino acid substitutions, and lowercase letters represent mixed populations.

Mentions: Cross-reactive vaccine-primed immune responses recognizing the infecting virus will likely determine the efficacy of HIV-1 vaccines. We therefore monitored cellular immune responses elicited by SIVmac239Δnef vaccination to determine which, if any, expanded after challenge with SIVsmE660. In IFN-γ ELISPOT assays using pools of peptides spanning the entire SIVmac239 proteome, we observed varying degrees of expansion in cellular immune responses above prechallenge levels at 2 wk p.c. (Fig. 3). Expanded responses were primarily directed against Gag and Pol, which are the most conserved proteins between SIVmac239Δnef and SIVsmE660 (Table I). To more closely examine the effect that amino acid changes within CD8+ T cell epitopes have on p.c. expansion, we used MHC-I–restricted peptides corresponding to the minimal optimal epitopes in SIVmac239Δnef. We found that some of the epitopes with 1 or 2 aa differences between SIVmac239Δnef and SIVsmE660 stimulated responses above prechallenge levels (Table II and Fig. S3 a, available at http://www.jem.org/cgi/content/full/jem.20081524/DC1). Correlating with the IFN-γ ELISPOT assays, some of the vaccinated animals displayed a twofold or more expansion of at least one tetramer binding population during acute infection (Fig. 4). Interestingly, the animals that controlled SIVsmE660 replication at 2 wk p.c. generally had the lowest frequency of p.c. cellular immune responses in the PBMC.


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)

Frequency of tetramer binding cells in the PBMC of SIVmac239Δnef-vaccinated macaques p.c. with SIVsmE660. (a) The frequency of MHC-I tetramer binding cells in the PBMC after challenge with SIVsmE660. Frequencies of tetramer positive cells are reported as the percentage of CD3+/CD8+/tetramer+ lymphocytes. The plasma virus concentrations for each animal are displayed with the red line and symbols. * distinguishes Nef221-229YY9 from Nef159-167YY9. (b) Comparison of amino acid sequences between SIVmac239-derived peptides and SIVsmE660. The SIVmac239 sequence is shown above SIVsmE660 sequence for comparison of the two viruses. Periods represent conserved amino acids, capital letters indicate amino acid substitutions, and lowercase letters represent mixed populations.
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Related In: Results  -  Collection

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fig4: Frequency of tetramer binding cells in the PBMC of SIVmac239Δnef-vaccinated macaques p.c. with SIVsmE660. (a) The frequency of MHC-I tetramer binding cells in the PBMC after challenge with SIVsmE660. Frequencies of tetramer positive cells are reported as the percentage of CD3+/CD8+/tetramer+ lymphocytes. The plasma virus concentrations for each animal are displayed with the red line and symbols. * distinguishes Nef221-229YY9 from Nef159-167YY9. (b) Comparison of amino acid sequences between SIVmac239-derived peptides and SIVsmE660. The SIVmac239 sequence is shown above SIVsmE660 sequence for comparison of the two viruses. Periods represent conserved amino acids, capital letters indicate amino acid substitutions, and lowercase letters represent mixed populations.
Mentions: Cross-reactive vaccine-primed immune responses recognizing the infecting virus will likely determine the efficacy of HIV-1 vaccines. We therefore monitored cellular immune responses elicited by SIVmac239Δnef vaccination to determine which, if any, expanded after challenge with SIVsmE660. In IFN-γ ELISPOT assays using pools of peptides spanning the entire SIVmac239 proteome, we observed varying degrees of expansion in cellular immune responses above prechallenge levels at 2 wk p.c. (Fig. 3). Expanded responses were primarily directed against Gag and Pol, which are the most conserved proteins between SIVmac239Δnef and SIVsmE660 (Table I). To more closely examine the effect that amino acid changes within CD8+ T cell epitopes have on p.c. expansion, we used MHC-I–restricted peptides corresponding to the minimal optimal epitopes in SIVmac239Δnef. We found that some of the epitopes with 1 or 2 aa differences between SIVmac239Δnef and SIVsmE660 stimulated responses above prechallenge levels (Table II and Fig. S3 a, available at http://www.jem.org/cgi/content/full/jem.20081524/DC1). Correlating with the IFN-γ ELISPOT assays, some of the vaccinated animals displayed a twofold or more expansion of at least one tetramer binding population during acute infection (Fig. 4). Interestingly, the animals that controlled SIVsmE660 replication at 2 wk p.c. generally had the lowest frequency of p.c. cellular immune responses in the PBMC.

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