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Maintenance or emergence of chronic phase secondary cytotoxic T lymphocyte responses after loss of acute phase immunodominant responses does not protect SIV-infected rhesus macaques from disease progression.

Keckler MS, Hodara VL, Parodi LM, Giavedoni LD - J. Biomed. Biotechnol. (2010)

Bottom Line: The simian immunodeficiency virus- (SIV-) infected rhesus macaque is the preferred animal model for vaccine development, but the correlates of protection in this model are not completely understood.Collectively, our data (1) identify novel CTL epitopes from an SP animal that are not restricted by known protective alleles, (2) illustrate that, in this small study, RP and NP animals accrue more mutations in CTL epitopes than in SP or LTNP macaques, and (3) demonstrate that the loss of CTL responses to immunodominant epitopes is associated with viral replication increases, which are not controlled by secondary CTL responses.These findings provide further evidence for the critical role of the primary cell-mediated immune responses in the control of retroviral infections.

View Article: PubMed Central - PubMed

Affiliation: University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

ABSTRACT
The simian immunodeficiency virus- (SIV-) infected rhesus macaque is the preferred animal model for vaccine development, but the correlates of protection in this model are not completely understood. In this paper, we document the cytotoxic T lymphocyte (CTL) response to SIV and its effects on viral evolution in an effort to identify events associated with disease progression regardless of MHC allele expression. We observed the evolution of epitopes targeted by CTLs in a group of macaques that included long-term nonprogressing (LTNP), slowly progressing (SP), normally progressing (NP), and rapidly progressing (RP) animals. Collectively, our data (1) identify novel CTL epitopes from an SP animal that are not restricted by known protective alleles, (2) illustrate that, in this small study, RP and NP animals accrue more mutations in CTL epitopes than in SP or LTNP macaques, and (3) demonstrate that the loss of CTL responses to immunodominant epitopes is associated with viral replication increases, which are not controlled by secondary CTL responses. These findings provide further evidence for the critical role of the primary cell-mediated immune responses in the control of retroviral infections.

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Viral Evolution in an Animal with Known Protective Mamu Alleles. (a) Comparison of IFN-γ ELISPOT values for the vaccinated, Mamu A*01+ NP animal 16040 before or after the Mamu A*01-restricted Gag CTPYDINQM to CIPYDINQM, Tat STPESANL to PTPESANP, and Pol STPPLVRLV to SSPPLVRLV mutations. Statistical analysis was performed using the Mann Whitney test. (b) NASBA viral loads and IFN-γ ELISPOT results for all three epitopes were plotted to determine the effects of mutations on the control of viral replication.
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fig2: Viral Evolution in an Animal with Known Protective Mamu Alleles. (a) Comparison of IFN-γ ELISPOT values for the vaccinated, Mamu A*01+ NP animal 16040 before or after the Mamu A*01-restricted Gag CTPYDINQM to CIPYDINQM, Tat STPESANL to PTPESANP, and Pol STPPLVRLV to SSPPLVRLV mutations. Statistical analysis was performed using the Mann Whitney test. (b) NASBA viral loads and IFN-γ ELISPOT results for all three epitopes were plotted to determine the effects of mutations on the control of viral replication.

Mentions: Not all animals harbouring the protective Mamu A*01 allele were able to control SIV infection. Sequencing of the viral epitopes in the Mamu A*01+ 16040 animal that progressed to SAIDS at 118 weeks post-challenge indicated that a threonine (T) to isoleucine (I) mutation was first observed in position 2 of the Gag CTPYDINQM epitope at 70 WPC. This is a well characterized escape mutation known to abrogate MHC binding [26] and was associated with a significant decrease in CTL response (Figure 2(a)). Other known escape mutations were first detected at 48 WPC in position 1 and 8 of the Tat STPESANL epitope (serine to proline, and leucine to proline) and these have also been reported to abrogate MHC binding [26]. This is consistent with declining numbers of CTLs specific for the wild-type epitope, which would be expected in animals no longer carrying virus with wild-type sequence. Interestingly, a threonine (T) to serine (S) mutation was observed in position 2 of the Mamu A*01 Pol STPPLVRLV epitope prior to 48WPC, but was not associated with a decrease in CTL response (Figure 2(a)). Analysis of viral loads (Figure 2(b)) illustrated that the Pol STPPLVRLV epitope was not protective as the viral load increased despite a CTL response to this epitope.


Maintenance or emergence of chronic phase secondary cytotoxic T lymphocyte responses after loss of acute phase immunodominant responses does not protect SIV-infected rhesus macaques from disease progression.

Keckler MS, Hodara VL, Parodi LM, Giavedoni LD - J. Biomed. Biotechnol. (2010)

Viral Evolution in an Animal with Known Protective Mamu Alleles. (a) Comparison of IFN-γ ELISPOT values for the vaccinated, Mamu A*01+ NP animal 16040 before or after the Mamu A*01-restricted Gag CTPYDINQM to CIPYDINQM, Tat STPESANL to PTPESANP, and Pol STPPLVRLV to SSPPLVRLV mutations. Statistical analysis was performed using the Mann Whitney test. (b) NASBA viral loads and IFN-γ ELISPOT results for all three epitopes were plotted to determine the effects of mutations on the control of viral replication.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2877203&req=5

fig2: Viral Evolution in an Animal with Known Protective Mamu Alleles. (a) Comparison of IFN-γ ELISPOT values for the vaccinated, Mamu A*01+ NP animal 16040 before or after the Mamu A*01-restricted Gag CTPYDINQM to CIPYDINQM, Tat STPESANL to PTPESANP, and Pol STPPLVRLV to SSPPLVRLV mutations. Statistical analysis was performed using the Mann Whitney test. (b) NASBA viral loads and IFN-γ ELISPOT results for all three epitopes were plotted to determine the effects of mutations on the control of viral replication.
Mentions: Not all animals harbouring the protective Mamu A*01 allele were able to control SIV infection. Sequencing of the viral epitopes in the Mamu A*01+ 16040 animal that progressed to SAIDS at 118 weeks post-challenge indicated that a threonine (T) to isoleucine (I) mutation was first observed in position 2 of the Gag CTPYDINQM epitope at 70 WPC. This is a well characterized escape mutation known to abrogate MHC binding [26] and was associated with a significant decrease in CTL response (Figure 2(a)). Other known escape mutations were first detected at 48 WPC in position 1 and 8 of the Tat STPESANL epitope (serine to proline, and leucine to proline) and these have also been reported to abrogate MHC binding [26]. This is consistent with declining numbers of CTLs specific for the wild-type epitope, which would be expected in animals no longer carrying virus with wild-type sequence. Interestingly, a threonine (T) to serine (S) mutation was observed in position 2 of the Mamu A*01 Pol STPPLVRLV epitope prior to 48WPC, but was not associated with a decrease in CTL response (Figure 2(a)). Analysis of viral loads (Figure 2(b)) illustrated that the Pol STPPLVRLV epitope was not protective as the viral load increased despite a CTL response to this epitope.

Bottom Line: The simian immunodeficiency virus- (SIV-) infected rhesus macaque is the preferred animal model for vaccine development, but the correlates of protection in this model are not completely understood.Collectively, our data (1) identify novel CTL epitopes from an SP animal that are not restricted by known protective alleles, (2) illustrate that, in this small study, RP and NP animals accrue more mutations in CTL epitopes than in SP or LTNP macaques, and (3) demonstrate that the loss of CTL responses to immunodominant epitopes is associated with viral replication increases, which are not controlled by secondary CTL responses.These findings provide further evidence for the critical role of the primary cell-mediated immune responses in the control of retroviral infections.

View Article: PubMed Central - PubMed

Affiliation: University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229-3900, USA.

ABSTRACT
The simian immunodeficiency virus- (SIV-) infected rhesus macaque is the preferred animal model for vaccine development, but the correlates of protection in this model are not completely understood. In this paper, we document the cytotoxic T lymphocyte (CTL) response to SIV and its effects on viral evolution in an effort to identify events associated with disease progression regardless of MHC allele expression. We observed the evolution of epitopes targeted by CTLs in a group of macaques that included long-term nonprogressing (LTNP), slowly progressing (SP), normally progressing (NP), and rapidly progressing (RP) animals. Collectively, our data (1) identify novel CTL epitopes from an SP animal that are not restricted by known protective alleles, (2) illustrate that, in this small study, RP and NP animals accrue more mutations in CTL epitopes than in SP or LTNP macaques, and (3) demonstrate that the loss of CTL responses to immunodominant epitopes is associated with viral replication increases, which are not controlled by secondary CTL responses. These findings provide further evidence for the critical role of the primary cell-mediated immune responses in the control of retroviral infections.

Show MeSH
Related in: MedlinePlus