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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 after SIVsmE660 challenge. (a) Plasma virus concentrations of the ten SIVmac239Δnef-vaccinated macaques and their ten MHC-I–matched naive controls. (b) Geometric means for the ten vaccinated and ten naive controls. (c) Plasma virus concentrations of the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (d) Geometric means for the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (e) Plasma virus concentrations of the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques. (f) Geometric means for the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques.
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fig1: Plasma virus concentrations after SIVsmE660 challenge. (a) Plasma virus concentrations of the ten SIVmac239Δnef-vaccinated macaques and their ten MHC-I–matched naive controls. (b) Geometric means for the ten vaccinated and ten naive controls. (c) Plasma virus concentrations of the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (d) Geometric means for the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (e) Plasma virus concentrations of the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques. (f) Geometric means for the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques.

Mentions: During acute infection, the SIVmac239Δnef-vaccinated animals reduced plasma virus concentrations by 2–3 logs in comparison to the naive controls (Fig. 1, a and b). At 2 (P = 0.011), 3 (P < 0.001), and 4 (P = 0.005) wk postchallenge (p.c.), the mean plasma virus concentrations in the vaccinated animals were significantly lower than that of the naive controls. The vaccinated animals maintained a reduction in mean plasma virus concentrations through 8 mo p.c. (the point at which some animals began experiencing simian AIDS). Only at week 24 p.c. did the difference in viral loads fall below the level of significance (P = 0.052). Despite gradually increasing plasma virus levels in some of the vaccinees, the majority of the time points showed significant difference between vaccines and controls (weeks p.c.: 6, P < 0.001; 8, P = 0.001; 12, P = 005; 16, P = 0.002; 20, P = 0.049; 28, P = 0.046; and 32, P = 0.008).


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 after SIVsmE660 challenge. (a) Plasma virus concentrations of the ten SIVmac239Δnef-vaccinated macaques and their ten MHC-I–matched naive controls. (b) Geometric means for the ten vaccinated and ten naive controls. (c) Plasma virus concentrations of the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (d) Geometric means for the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (e) Plasma virus concentrations of the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques. (f) Geometric means for the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques.
© Copyright Policy
Related In: Results  -  Collection

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

fig1: Plasma virus concentrations after SIVsmE660 challenge. (a) Plasma virus concentrations of the ten SIVmac239Δnef-vaccinated macaques and their ten MHC-I–matched naive controls. (b) Geometric means for the ten vaccinated and ten naive controls. (c) Plasma virus concentrations of the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (d) Geometric means for the vaccinated and naive Mamu-B*08+ and -B*17+ macaques. (e) Plasma virus concentrations of the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques. (f) Geometric means for the vaccinated and naive Mamu-A*01+, -A*02+, and -A*11+ macaques.
Mentions: During acute infection, the SIVmac239Δnef-vaccinated animals reduced plasma virus concentrations by 2–3 logs in comparison to the naive controls (Fig. 1, a and b). At 2 (P = 0.011), 3 (P < 0.001), and 4 (P = 0.005) wk postchallenge (p.c.), the mean plasma virus concentrations in the vaccinated animals were significantly lower than that of the naive controls. The vaccinated animals maintained a reduction in mean plasma virus concentrations through 8 mo p.c. (the point at which some animals began experiencing simian AIDS). Only at week 24 p.c. did the difference in viral loads fall below the level of significance (P = 0.052). Despite gradually increasing plasma virus levels in some of the vaccinees, the majority of the time points showed significant difference between vaccines and controls (weeks p.c.: 6, P < 0.001; 8, P = 0.001; 12, P = 005; 16, P = 0.002; 20, P = 0.049; 28, P = 0.046; and 32, P = 0.008).

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