Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8<sup>+</sup>T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

Ayala, Victor I.; Trivett, Matthew T.; Barsov, Eugene V.; Jain, Sumiti; Piatak, Michael; Trubey, Charles M.; Alvord, W. Gregory; Chertova, Elena; Roser, James D.; Smedley, Jeremy; Komin, Alexander; Keele, Brandon F.; Ott, David E.

doi:10.1128/jvi.01522-16

Cited by 14 publications

(26 citation statements)

References 55 publications

(80 reference statements)

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“…Other adoptive transfer studies relying on longer, more extensive in vitro selection and expansion of naturally occurring SIV-specific T-cell clones in culture rather than the limited ex vivo expansion made possible by engineering T cells presented here have observed no detectable persistence in either blood or tissues other than the lung (47,48). Recently, we applied T-cell engineering techniques to express CCR7/CD62L on T cells and observed limited, but unequivocal trafficking to lymph nodes and avoidance of the lung, demonstrating targeting of infused T cells to lymphoid tissues in a nonhuman primate system (43). Here, we extend this concept with cells that had less extensive expansion ex vivo than used in our prior CCR7/CD62L study, and we observed greater frequencies of infused cells in the secondary lymphoid tissues.…”

Section: Discussionmentioning

confidence: 81%

“…The frequencies of the infused T cells in PBMC from necropsy samples were decreased approximately 10-fold from those of the 15-min postinfusion samples, ranging from 0.3 to 1% (n ϭ 6; x ϭ 0.7%; SD ϭ 0.25%), suggesting movement of the infused cells out of the peripheral circulatory system. One common observation in adoptive transfer studies is that bronchoalveolar lavage sampling of animals contain high frequencies of infused cells, presumed to be "trapped" in the lung (43,47,48). Flow cytometry of CD3 ϩ cells isolated from the prenecropsy bronchoalveolar lavage samples showed a high frequency of infused cells relative to the endog- enous T cells, from 7 to 76% (n ϭ 6; x ϭ 54%; SD ϭ 24%) consistent with retention of some of the infused cells in the lung.…”

Section: Resultsmentioning

confidence: 99%

“…The ability to genetically engineer T cells with genes of interest, especially T-cell receptors (TCR) and chimeric antigen receptors, using retroviral and lentiviral vectors is a powerful technique, from the initial human gene therapy trial 25 years ago to its current use in cellular immunotherapeutics against cancer (40)(41)(42). In a pilot study, we engineered SIV-specific T cells with CCR7 and CD62L which preferentially localized to lymph nodes in a rhesus macaque adoptive transfer system (43). For this study, we tested whether circulating CD8 T cells can be engineered to enter B-cell follicles in rhesus macaques by ectopically expressing CXCR5 on unselected bulk peripheral blood-derived CD8 T cells, expanding the engineered T cells ex vivo, and infusing the autologous cells back into donor animals.…”

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confidence: 99%

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CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

Ayala

Deléage

Trivett

et al. 2017

J Virol

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Follicular helper CD4 T cells, T, residing in B-cell follicles within secondary lymphoid tissues, are readily infected by AIDS viruses and are a major source of persistent virus despite relative control of viral replication. This persistence is due at least in part to a relative exclusion of effective antiviral CD8 T cells from B-cell follicles. To determine whether CD8 T cells could be engineered to enter B-cell follicles, we genetically modified unselected CD8 T cells to express CXC chemokine receptor 5 (CXCR5), the chemokine receptor implicated in cellular entry into B-cell follicles. Engineered CD8 T cells expressing human CXCR5 (CD8) exhibited ligand-specific signaling and chemotaxis Six infected rhesus macaques were infused with differentially fluorescent dye-labeled autologous CD8 and untransduced CD8 T cells and necropsied 48 h later. Flow cytometry of both spleen and lymph node samples revealed higher frequencies of CD8 than untransduced cells, consistent with preferential trafficking to B-cell follicle-containing tissues. Confocal fluorescence microscopy of thin-sectioned lymphoid tissues demonstrated strong preferential localization of CD8 T cells within B-cell follicles with only rare cells in extrafollicular locations. CD8 T cells were present throughout the follicles with some observed near infected T In contrast, untransduced CD8 T cells were found in the extrafollicular T-cell zone. Our ability to direct localization of unselected CD8 T cells into B-cell follicles using CXCR5 expression provides a strategy to place highly effective virus-specific CD8 T cells into these AIDS virus sanctuaries and potentially suppress residual viral replication. AIDS virus persistence in individuals under effective drug therapy or those who spontaneously control viremia remains an obstacle to definitive treatment. Infected follicular helper CD4 T cells, T, present inside B-cell follicles represent a major source of this residual virus. While effective CD8 T-cell responses can control viral replication in conjunction with drug therapy or in rare cases spontaneously, most antiviral CD8 T cells do not enter B-cell follicles, and those that do fail to robustly control viral replication in the T population. Thus, these sites are a sanctuary and a reservoir for replicating AIDS viruses. Here, we demonstrate that engineering unselected CD8 T cells to express CXCR5, a chemokine receptor on T associated with B-cell follicle localization, redirects them into B-cell follicles. These proof of principle results open a pathway for directing engineered antiviral T cells into these viral sanctuaries to help eliminate this source of persistent virus.

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Section: Discussionmentioning

confidence: 81%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

Ayala

Deléage

Trivett

et al. 2017

J Virol

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“…17 Meanwhile, experiments designed to change the numbers of CD8+ T cells in circulation have an important (but variable) impact on viral load. These include experiments to increase the number of CD8+ T cells, such as infusion of these cells [18][19][20][21][22][23][24] and studies of vaccines leading to large expansions of the circulating CD8+ T-cell counts. 25,26 The opposite approach, trying to reduce CD8+ cells, by infusion of depleting antibodies, has also been attempted in simian immunodeficiency virus (SIV) animal models, usually leading to significant increases in viral load.…”

Section: Cells 11mentioning

confidence: 99%

The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

Cardozo

Apetrei

Pandrea

et al. 2018

Immunological Reviews

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Human immunodeficiency virus infection is still one of the most important causes of morbidity and mortality in the world, with a disproportionate human and economic burden especially in poorer countries. Despite many years of intense research, an aspect that still is not well understood is what (immune) mechanisms control the viral load during the prolonged asymptomatic stage of infection. Because CD8+ T cells have been implicated in this control by multiple lines of evidence, there has been a focus on understanding the potential mechanisms of action of this immune effector population. One type of experiment used to this end has been depleting these cells with monoclonal antibodies in the simian immunodeficiency virus-macaque model and then studying the effect of that depletion on the viral dynamics. Here we review what these experiments have told us. We emphasize modeling studies to interpret the changes in viral load observed in these experiments, including discussion of alternative models, assumptions and interpretations, as well as potential future experiments.

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“…Indeed, mounting evidence suggests that lentivirus-specific CD8 ϩ T cells can do more than reduce viremia in productively infected individuals. For instance, a recent study has shown that adoptively transferring large quantities of SIV-specific CD8 ϩ T cells into RMs 3 days after a high-dose IR challenge with SIV can reduce the number of transmitted/founder viruses in infected animals (56). Although this approach did not prevent the establishment of productive infection, it lends support to the notion that high frequencies of vaccine-elicited CD8 ϩ T cells situated at relevant sites of virus replication can intercept a nascent infection before it becomes systemic.…”

Section: Discussionmentioning

confidence: 99%

The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B08 ⁺* Rhesus Macaques

Martins

Gonzalez-Nieto

Shin

et al. 2019

J Virol

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Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) alleleMamu-B*08spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8+T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infectedMamu-B*08-positive (Mamu-B*08+) RMs. Here we evaluated if robust vaccine-elicited CD8+T-cell responses against Vif and Nef can prevent systemic infection inMamu-B*08+RMs following mucosal SIV challenges. TenMamu-B*08+RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8+T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection.IMPORTANCEIt is generally accepted that the antiviral effects of vaccine-induced classical CD8+T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8+T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.

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Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8⁺T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

Cited by 14 publications

References 55 publications

CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B08 ⁺* Rhesus Macaques

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Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8+T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

Cited by 14 publications

References 55 publications

CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

CXCR5-Dependent Entry of CD8 T Cells into Rhesus Macaque B-Cell Follicles Achieved through T-Cell Engineering

The dynamics of simian immunodeficiency virus after depletion of CD8+ cells

The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B*08 + Rhesus Macaques

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Adoptive Transfer of Engineered Rhesus Simian Immunodeficiency Virus-Specific CD8⁺T Cells Reduces the Number of Transmitted/Founder Viruses Established in Rhesus Macaques

The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B08 ⁺* Rhesus Macaques