Multispecific Vaccine-Induced Mucosal Cytotoxic TLymphocytes Reduce Acute-Phase Viral Replication but Fail inLong-Term Control of Simian Immunodeficiency VirusSIVmac239

Vogel, Thorsten U.; Reynolds, Matthew R.; Fuller, Deborah H.; Vielhuber, Kathy; Shipley, Tim; Fuller, James T.; Kunstman, Kevin; Sutter, Gerd; Marthas, Marta; Erfle, Volker; Wolinsky, Steven M.; Wang, Chenxi; Allison, David B.; Rud, Erling W.; Wilson, Nancy A.; Montefiori, David C.; Altman, John D.; Watkins, David I.

doi:10.1128/jvi.77.24.13348-13360.2003

Cited by 93 publications

(78 citation statements)

References 58 publications

(75 reference statements)

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“…8); we excluded this animal from further analysis because of its uncertain infection status. We concluded, based on these results, that none of the SIV immunization regimens used results in significant protection from SIV mac239 transmission, and these findings are consistent with previous preclinical studies of CTL-based immunogens that do not contain an Env antigen (20,21).…”

Section: Resultssupporting

confidence: 78%

Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Carnathan

Wetzel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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An effective T-cell–based AIDS vaccine should induce strong HIV-specific CD8+ T cells in mucosal tissues without increasing the availability of target cells for the virus. Here, we evaluated five immunization strategies that include Human adenovirus-5 (AdHu5), Chimpanzee adenovirus-6 (AdC6) or -7 (AdC7), Vaccinia virus (VV), and DNA given by electroporation (DNA/EP), all expressing Simian immunodeficiency virus group specific antigen/transactivator of transcription (SIVmac239Gag/Tat). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EP-VV-AdC6, DNA/EP-VV-AdC7, or AdHu5-AdHu5-AdHu5 and were challenged repeatedly with low-dose intrarectal SIVmac239. Upon challenge, there were no significant differences among study groups in terms of virus acquisition or viral load after infection. When taken together, the immunization regimens did not protect against SIV acquisition compared with controls but did result in an ∼1.6-log decline in set-point viremia. Although all immunized RMs had detectable SIV-specific CD8+ T cells in blood and rectal mucosa, we found no correlation between the number or function of these SIV-specific CD8+ T cells and protection against SIV acquisition. Interestingly, RMs experiencing breakthrough infection showed significantly higher prechallenge levels of CD4+C-C chemokine receptor type 5 (CCR5)+HLA-DR+ T cells in the rectal biopsies (RB) than animals that remained uninfected. In addition, among the infected RMs, the percentage of CD4+CCR5+Ki-67+ T cells in RBs prechallenge correlated with higher early viremia. Overall, these data suggest that the levels of activated CD4+CCR5+ target T cells in the rectal mucosa may predict the risk of SIV acquisition in RMs vaccinated with vectors that express SIVGag/Tat.

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Section: Resultssupporting

confidence: 78%

Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Carnathan

Wetzel

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…2A). Consistent with previous studies (26,27), the magnitude of Gag-specific responses was higher than Tat-specific throughout the follow-up period. Although it appears that the MVA-SIV vaccine vector induced slightly higher prechallenge Gag-specific responses, these differences were not significant.…”

Section: Mva-siv and Mva⌬udg-siv Induced Strong Levels Of Siv-specifisupporting

confidence: 80%

“…26). In contrast, in another study (27), a more persistent (Ͼ1 year) and robust suppression of SIV replication was observed in MamuA*01…”

Section: Discussionmentioning

confidence: 69%

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

Engram

Dunham

Makedonas

et al. 2009

The Journal of Immunology

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Our limited understanding of the interaction between primate lentiviruses and the host immune system complicates the design of an effective HIV/AIDS vaccine. To identify immunological correlates of protection from SIV disease progression, we immunized two groups of five rhesus macaques (RMs) with either modified vaccinia Ankara (MVA) or MVAΔudg vectors that expressed SIVmac239 Gag and Tat. Both vectors raised a SIV-specific CD8+ T cell response, with a magnitude that was greater in mucosal tissues than in peripheral blood. After challenge with SIVmac239, all vaccinated RMs showed mucosal and systemic CD8+ T cell recall responses that appeared faster and were of greater magnitude than those in five unvaccinated control animals. All vaccinated RMs showed a ∼1-log lower peak and early set-point SIV viral load than the unvaccinated animals, and then, by 8 wk postchallenge, exhibited levels of viremia similar to the controls. We observed a significant direct correlation between the magnitude of postchallenge SIV-specific CD8+ T cell responses and SIV viral load. However, vaccinated RMs showed no protection from either systemic or mucosal CD4+ T cell depletion and no improved survival. The observation that vaccine-induced, SIV-specific CD8+ T cells that partially control SIVmac239 virus replication fail to protect from immunological or clinical progression of SIV infection underscores both the complexity of AIDS pathogenesis and the challenges of properly assessing the efficacy of candidate AIDS vaccines.

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“…Our finding that challenge with the highly pathogenic SHIV virus enhances cellular immunity confirms the results of a recent study (41). It has been demonstrated that HIV-specific CD8 ϩ T cell responses play an important role in controlling viral replication by cytolysis and cytokine and/or anti-virus factor production (1,2,3,42,43).…”

Section: Discussionsupporting

confidence: 81%

“…In some macaque HIV/AIDS models, SIVmac239 has been targeted as a desirable challenge virus, because it is a typical CCR5-tropic SIVmac and can cause both chronic and progressive disease in macaques (41,58,59). However, the virus is very difficult to neutralize and also very difficult to clear even from animals that have been previously immunized with homologous recombinant vector-based vaccines (41,58,59). Only live attenuated SIV has been reported to control SIVmac239 (T. Allen, Global HIV Vaccine Enterprise Meeting, Washington, October 21, 2004).…”

Section: Discussionmentioning

confidence: 99%

Induction of Positive Cellular and Humoral Immune Responses by a Prime-Boost Vaccine Encoded with Simian Immunodeficiency Virusgag/pol

Someya

Ami

Nakasone

et al. 2006

The Journal of Immunology

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It is believed likely that immune responses are responsible for controlling viral load and infection. In this study, when macaques were primed with plasmid DNA encoding SIV gag and pol genes (SIVgag/pol DNA) and then boosted with replication-deficient vaccinia virus DIs recombinant expressing the same genes (rDIsSIVgag/pol), this prime-boost regimen generated higher levels of Gag-specific CD4+ and CD8+ T cell responses than did either SIVgag/pol DNA or rDIsSIVgag/pol alone. When the macaques were i.v. challenged with pathogenic simian/HIV, the prime-boost group maintained high CD4+ T cell counts and reduced plasma viral loads up to 30 wk after viral challenge, whereas the rDIsSIVgag/pol group showed only a partial attenuation of the viral infection, and the group immunized with SIVgag/pol DNA alone showed none at all. The protection levels were better correlated with the levels of virus-specific T cell responses than the levels of neutralization Ab responses. These results demonstrate that a vaccine regimen that primes with DNA and then boosts with a replication-defective vaccinia virus DIs generates anti-SIV immunity, suggesting that it will be a promising vaccine regimen for HIV-1 vaccine development.

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Multispecific Vaccine-Induced Mucosal Cytotoxic TLymphocytes Reduce Acute-Phase Viral Replication but Fail inLong-Term Control of Simian Immunodeficiency VirusSIVmac239

Cited by 93 publications

References 58 publications

Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

Induction of Positive Cellular and Humoral Immune Responses by a Prime-Boost Vaccine Encoded with Simian Immunodeficiency Virusgag/pol

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Multispecific Vaccine-Induced Mucosal Cytotoxic TLymphocytes Reduce Acute-Phase Viral Replication but Fail inLong-Term Control of Simian Immunodeficiency VirusSIVmac239

Cited by 93 publications

References 58 publications

Activated CD4 + CCR5 + T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Activated CD4 + CCR5 + T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Vaccine-Induced, Simian Immunodeficiency Virus-Specific CD8+ T Cells Reduce Virus Replication but Do Not Protect from Simian Immunodeficiency Virus Disease Progression

Induction of Positive Cellular and Humoral Immune Responses by a Prime-Boost Vaccine Encoded with Simian Immunodeficiency Virusgag/pol

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Product

Resources

About

Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques