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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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No in vitro neutralization of SIVsmE660 by vaccine-induced antibodies. Percent neutralization of SIVsmE660 replication in rhesus macaque PBMC after 7 d in culture by plasma collected before challenge in SIVmac239Δnef vaccinees. The chimeric molecule CD4-IgG2 was used as a positive control for neutralization and plasma collected from an unvaccinated animal, 84070, before challenge was used as a negative control. Percent neutralization is presented as the reduction in the amount of virus at the end of the assay in comparison to cells infected with SIVsmE660 alone. Similar negative plasma neutralization results were observed in a TZM-bl cell neutralization assay (65). Error bars represent SEM of experiments done in triplicate.
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fig2: No in vitro neutralization of SIVsmE660 by vaccine-induced antibodies. Percent neutralization of SIVsmE660 replication in rhesus macaque PBMC after 7 d in culture by plasma collected before challenge in SIVmac239Δnef vaccinees. The chimeric molecule CD4-IgG2 was used as a positive control for neutralization and plasma collected from an unvaccinated animal, 84070, before challenge was used as a negative control. Percent neutralization is presented as the reduction in the amount of virus at the end of the assay in comparison to cells infected with SIVsmE660 alone. Similar negative plasma neutralization results were observed in a TZM-bl cell neutralization assay (65). Error bars represent SEM of experiments done in triplicate.

Mentions: Interestingly, we found no evidence that vaccine-induced neutralizing antibodies contributed to the control of viral replication. We assessed the level of preexisting neutralizing antibodies in the plasma of two animals that controlled acute or chronic virus replication (01022 and 01003) and two animals that did not control virus replication p.c. (rhAO84 and rh2000). None of the animals had any neutralizing antibody activity against SIVsmE660 (Fig. 2). This indicates that cellular immune responses likely play the main role for controlling virus replication after heterologous virus challenge.


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)

No in vitro neutralization of SIVsmE660 by vaccine-induced antibodies. Percent neutralization of SIVsmE660 replication in rhesus macaque PBMC after 7 d in culture by plasma collected before challenge in SIVmac239Δnef vaccinees. The chimeric molecule CD4-IgG2 was used as a positive control for neutralization and plasma collected from an unvaccinated animal, 84070, before challenge was used as a negative control. Percent neutralization is presented as the reduction in the amount of virus at the end of the assay in comparison to cells infected with SIVsmE660 alone. Similar negative plasma neutralization results were observed in a TZM-bl cell neutralization assay (65). Error bars represent SEM of experiments done in triplicate.
© Copyright Policy
Related In: Results  -  Collection

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

fig2: No in vitro neutralization of SIVsmE660 by vaccine-induced antibodies. Percent neutralization of SIVsmE660 replication in rhesus macaque PBMC after 7 d in culture by plasma collected before challenge in SIVmac239Δnef vaccinees. The chimeric molecule CD4-IgG2 was used as a positive control for neutralization and plasma collected from an unvaccinated animal, 84070, before challenge was used as a negative control. Percent neutralization is presented as the reduction in the amount of virus at the end of the assay in comparison to cells infected with SIVsmE660 alone. Similar negative plasma neutralization results were observed in a TZM-bl cell neutralization assay (65). Error bars represent SEM of experiments done in triplicate.
Mentions: Interestingly, we found no evidence that vaccine-induced neutralizing antibodies contributed to the control of viral replication. We assessed the level of preexisting neutralizing antibodies in the plasma of two animals that controlled acute or chronic virus replication (01022 and 01003) and two animals that did not control virus replication p.c. (rhAO84 and rh2000). None of the animals had any neutralizing antibody activity against SIVsmE660 (Fig. 2). This indicates that cellular immune responses likely play the main role for controlling virus replication after heterologous virus challenge.

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