Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial

Sergio Serrano-Villar, Talia Sainz, Zhong Min Ma, Netanya S. Utay, Tae Wook-Chun, Surinder Mann, Angela D. Kashuba, Basile Siewe, Anthony Albanese, Paolo Troia-Cancio, Elizabeth Sinclair, Anoma Somasunderam, Tammy Yotter, Steven G. Deeks, Alan Landay, Richard B. Pollard, Christopher J. Miller, Santiago Moreno, David M. Asmuth

Research output: Contribution to journalArticle

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Abstract

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

Original languageEnglish (US)
Article numbere1005381
JournalPLoS Pathogens
Volume12
Issue number1
DOIs
StatePublished - 2016

Fingerprint

Integrase Inhibitors
Mucosal Immunity
HIV
T-Lymphocytes
T-Lymphocyte Subsets
Tenofovir
efavirenz
Duodenum
Therapeutics
Immunity
Cell Count
Pharmaceutical Preparations
Biopsy
CD4-CD8 Ratio
DNA
Lymphoid Tissue
HLA-DR Antigens
Interleukin-6
Mass Spectrometry
Flow Cytometry

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy : A Pilot Randomized Trial. / Serrano-Villar, Sergio; Sainz, Talia; Ma, Zhong Min; Utay, Netanya S.; Wook-Chun, Tae; Mann, Surinder; Kashuba, Angela D.; Siewe, Basile; Albanese, Anthony; Troia-Cancio, Paolo; Sinclair, Elizabeth; Somasunderam, Anoma; Yotter, Tammy; Deeks, Steven G.; Landay, Alan; Pollard, Richard B.; Miller, Christopher J.; Moreno, Santiago; Asmuth, David M.

In: PLoS Pathogens, Vol. 12, No. 1, e1005381, 2016.

Research output: Contribution to journalArticle

Serrano-Villar, S, Sainz, T, Ma, ZM, Utay, NS, Wook-Chun, T, Mann, S, Kashuba, AD, Siewe, B, Albanese, A, Troia-Cancio, P, Sinclair, E, Somasunderam, A, Yotter, T, Deeks, SG, Landay, A, Pollard, RB, Miller, CJ, Moreno, S & Asmuth, DM 2016, 'Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial', PLoS Pathogens, vol. 12, no. 1, e1005381. https://doi.org/10.1371/journal.ppat.1005381
Serrano-Villar, Sergio ; Sainz, Talia ; Ma, Zhong Min ; Utay, Netanya S. ; Wook-Chun, Tae ; Mann, Surinder ; Kashuba, Angela D. ; Siewe, Basile ; Albanese, Anthony ; Troia-Cancio, Paolo ; Sinclair, Elizabeth ; Somasunderam, Anoma ; Yotter, Tammy ; Deeks, Steven G. ; Landay, Alan ; Pollard, Richard B. ; Miller, Christopher J. ; Moreno, Santiago ; Asmuth, David M. / Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy : A Pilot Randomized Trial. In: PLoS Pathogens. 2016 ; Vol. 12, No. 1.
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abstract = "Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-na{\"i}ve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the na{\"i}ve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, {\%}CD4+ and {\%}CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal na{\"i}ve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment na{\"i}ve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.",
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AU - Serrano-Villar, Sergio

AU - Sainz, Talia

AU - Ma, Zhong Min

AU - Utay, Netanya S.

AU - Wook-Chun, Tae

AU - Mann, Surinder

AU - Kashuba, Angela D.

AU - Siewe, Basile

AU - Albanese, Anthony

AU - Troia-Cancio, Paolo

AU - Sinclair, Elizabeth

AU - Somasunderam, Anoma

AU - Yotter, Tammy

AU - Deeks, Steven G.

AU - Landay, Alan

AU - Pollard, Richard B.

AU - Miller, Christopher J.

AU - Moreno, Santiago

AU - Asmuth, David M.

PY - 2016

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N2 - Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory markers and impact on HIV persistence by cell-dependent mechanisms, and show unique effects of MVC in duodenal immunity driven by higher drug tissue penetration and possibly by class-dependent effects.

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