Repeated vaginal SHIV challenges in macaques receiving oral or topical preexposure prophylaxis induce virus-specific T-cell responses

Theodros S. Tsegaye, Katherine Butler, Wei Luo, Jessica Ann Radzio-Basu, Priya Srinivasan, Sunita Sharma, Rachael D. Aubert, Debra L. Hanson, Charles Dobard, Jose Gerardo Garcia-Lerma, Walid Heneine, Janet M. McNicholl, Ellen N. Kersh

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Background: Preexposure prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that Simian/Human Immunodeficiency Virus chimera (SHIV)-specific T-cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T-cell chemovaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure. Methods: Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild-type (WT) SHIVSF162P3 (n = 24) or a clonal derivative with the tenofovir (TFV) K65R drug-resistant mutation (n = 12). PrEP consisted of oral Truvada (n = 6, WT), TFV vaginal gel (n = 6, K65R), or TFV intravaginal ring (n = 6, WT). The remaining animals were PrEPinexperienced controls (n = 12, WT; n = 6, K65R). SHIV-specific T cells were identified and characterized using interferon γ Enzyme-Linked ImmunoSpot (ELISPOT) and multiparameter flow cytometry. Results: Of 9 animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, 8 (88.9%) developed virusspecific T-cell responses. T cells were in CD4 and CD8 compartments, reached up to 4900 interferon γ-producing cells per million peripheral blood mononuclear cells, and primarily pol directed. In contrast, the replication-impaired K65R virus did not induce detectable T-cell responses, likely reflecting the need for adequate replication. Conclusions: Virus-specific T-cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and after PrEP warrants further investigation.

Original languageEnglish (US)
Pages (from-to)385-394
Number of pages10
JournalJournal of Acquired Immune Deficiency Syndromes
Volume69
Issue number4
DOIs
StatePublished - Jan 1 2015

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Simian Immunodeficiency Virus
Macaca
Tenofovir
HIV
Viruses
T-Lymphocytes
Macaca nemestrina
Interferons
Foams and Jellies Vaginal Creams
Pharmaceutical Preparations
Blood Cells
Flow Cytometry
Observation
Mutation
Enzymes
Infection

All Science Journal Classification (ASJC) codes

  • Infectious Diseases
  • Pharmacology (medical)

Cite this

Tsegaye, Theodros S. ; Butler, Katherine ; Luo, Wei ; Radzio-Basu, Jessica Ann ; Srinivasan, Priya ; Sharma, Sunita ; Aubert, Rachael D. ; Hanson, Debra L. ; Dobard, Charles ; Garcia-Lerma, Jose Gerardo ; Heneine, Walid ; McNicholl, Janet M. ; Kersh, Ellen N. / Repeated vaginal SHIV challenges in macaques receiving oral or topical preexposure prophylaxis induce virus-specific T-cell responses. In: Journal of Acquired Immune Deficiency Syndromes. 2015 ; Vol. 69, No. 4. pp. 385-394.
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title = "Repeated vaginal SHIV challenges in macaques receiving oral or topical preexposure prophylaxis induce virus-specific T-cell responses",
abstract = "Background: Preexposure prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that Simian/Human Immunodeficiency Virus chimera (SHIV)-specific T-cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T-cell chemovaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure. Methods: Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild-type (WT) SHIVSF162P3 (n = 24) or a clonal derivative with the tenofovir (TFV) K65R drug-resistant mutation (n = 12). PrEP consisted of oral Truvada (n = 6, WT), TFV vaginal gel (n = 6, K65R), or TFV intravaginal ring (n = 6, WT). The remaining animals were PrEPinexperienced controls (n = 12, WT; n = 6, K65R). SHIV-specific T cells were identified and characterized using interferon γ Enzyme-Linked ImmunoSpot (ELISPOT) and multiparameter flow cytometry. Results: Of 9 animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, 8 (88.9{\%}) developed virusspecific T-cell responses. T cells were in CD4 and CD8 compartments, reached up to 4900 interferon γ-producing cells per million peripheral blood mononuclear cells, and primarily pol directed. In contrast, the replication-impaired K65R virus did not induce detectable T-cell responses, likely reflecting the need for adequate replication. Conclusions: Virus-specific T-cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and after PrEP warrants further investigation.",
author = "Tsegaye, {Theodros S.} and Katherine Butler and Wei Luo and Radzio-Basu, {Jessica Ann} and Priya Srinivasan and Sunita Sharma and Aubert, {Rachael D.} and Hanson, {Debra L.} and Charles Dobard and Garcia-Lerma, {Jose Gerardo} and Walid Heneine and McNicholl, {Janet M.} and Kersh, {Ellen N.}",
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Tsegaye, TS, Butler, K, Luo, W, Radzio-Basu, JA, Srinivasan, P, Sharma, S, Aubert, RD, Hanson, DL, Dobard, C, Garcia-Lerma, JG, Heneine, W, McNicholl, JM & Kersh, EN 2015, 'Repeated vaginal SHIV challenges in macaques receiving oral or topical preexposure prophylaxis induce virus-specific T-cell responses', Journal of Acquired Immune Deficiency Syndromes, vol. 69, no. 4, pp. 385-394. https://doi.org/10.1097/QAI.0000000000000642

Repeated vaginal SHIV challenges in macaques receiving oral or topical preexposure prophylaxis induce virus-specific T-cell responses. / Tsegaye, Theodros S.; Butler, Katherine; Luo, Wei; Radzio-Basu, Jessica Ann; Srinivasan, Priya; Sharma, Sunita; Aubert, Rachael D.; Hanson, Debra L.; Dobard, Charles; Garcia-Lerma, Jose Gerardo; Heneine, Walid; McNicholl, Janet M.; Kersh, Ellen N.

In: Journal of Acquired Immune Deficiency Syndromes, Vol. 69, No. 4, 01.01.2015, p. 385-394.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Repeated vaginal SHIV challenges in macaques receiving oral or topical preexposure prophylaxis induce virus-specific T-cell responses

AU - Tsegaye, Theodros S.

AU - Butler, Katherine

AU - Luo, Wei

AU - Radzio-Basu, Jessica Ann

AU - Srinivasan, Priya

AU - Sharma, Sunita

AU - Aubert, Rachael D.

AU - Hanson, Debra L.

AU - Dobard, Charles

AU - Garcia-Lerma, Jose Gerardo

AU - Heneine, Walid

AU - McNicholl, Janet M.

AU - Kersh, Ellen N.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Background: Preexposure prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that Simian/Human Immunodeficiency Virus chimera (SHIV)-specific T-cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T-cell chemovaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure. Methods: Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild-type (WT) SHIVSF162P3 (n = 24) or a clonal derivative with the tenofovir (TFV) K65R drug-resistant mutation (n = 12). PrEP consisted of oral Truvada (n = 6, WT), TFV vaginal gel (n = 6, K65R), or TFV intravaginal ring (n = 6, WT). The remaining animals were PrEPinexperienced controls (n = 12, WT; n = 6, K65R). SHIV-specific T cells were identified and characterized using interferon γ Enzyme-Linked ImmunoSpot (ELISPOT) and multiparameter flow cytometry. Results: Of 9 animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, 8 (88.9%) developed virusspecific T-cell responses. T cells were in CD4 and CD8 compartments, reached up to 4900 interferon γ-producing cells per million peripheral blood mononuclear cells, and primarily pol directed. In contrast, the replication-impaired K65R virus did not induce detectable T-cell responses, likely reflecting the need for adequate replication. Conclusions: Virus-specific T-cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and after PrEP warrants further investigation.

AB - Background: Preexposure prophylaxis (PrEP) for HIV prevention is a novel biomedical prevention method. We have previously modeled PrEP during rectal SHIV exposures in macaques and identified that Simian/Human Immunodeficiency Virus chimera (SHIV)-specific T-cell responses were induced in the presence of antiretroviral drugs, an observation previously termed T-cell chemovaccination. This report expands those initial findings by examining a larger group of macaques that were given oral or topical PrEP during repeated vaginal virus exposure. Methods: Thirty-six female pigtail macaques received up to 20 repeat low-dose vaginal inoculations with wild-type (WT) SHIVSF162P3 (n = 24) or a clonal derivative with the tenofovir (TFV) K65R drug-resistant mutation (n = 12). PrEP consisted of oral Truvada (n = 6, WT), TFV vaginal gel (n = 6, K65R), or TFV intravaginal ring (n = 6, WT). The remaining animals were PrEPinexperienced controls (n = 12, WT; n = 6, K65R). SHIV-specific T cells were identified and characterized using interferon γ Enzyme-Linked ImmunoSpot (ELISPOT) and multiparameter flow cytometry. Results: Of 9 animals that were on PrEP and remained uninfected during WT SHIV vaginal challenges, 8 (88.9%) developed virusspecific T-cell responses. T cells were in CD4 and CD8 compartments, reached up to 4900 interferon γ-producing cells per million peripheral blood mononuclear cells, and primarily pol directed. In contrast, the replication-impaired K65R virus did not induce detectable T-cell responses, likely reflecting the need for adequate replication. Conclusions: Virus-specific T-cell responses occur frequently in oral or topical PrEP-protected pigtail macaques after vaginal exposure to WT SHIV virus. The contribution of such immune responses to protection from infection during and after PrEP warrants further investigation.

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