HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality

Sergio Serrano-Villar, Talia Sainz, Sulggi A. Lee, Peter W. Hunt, Elizabeth Sinclair, Barbara Shacklett, April L. Ferre, Timothy L. Hayes, Ma Somsouk, Priscilla Y. Hsue, Mark L. Van Natta, Curtis L. Meinert, Michael M. Lederman, Hiroyu Hatano, Vivek Jain, Yong Huang, Frederick M. Hecht, Jeffrey N. Martin, Joseph M. McCune, Santiago MorenoSteven G. Deeks

Research output: Contribution to journalArticle

225 Citations (Scopus)

Abstract

A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naïve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.

Original languageEnglish (US)
Article numbere1004078
JournalPLoS Pathogens
Volume10
Issue number5
DOIs
StatePublished - 2014

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CD4-CD8 Ratio
T-Lymphocyte Subsets
HIV
Morbidity
T-Lymphocytes
Mortality
CD4 Lymphocyte Count
Phenotype
Therapeutics
Kynurenine
Tryptophan
Longitudinal Studies
Mucous Membrane
Lymph Nodes
Clinical Trials
Infection

ASJC Scopus subject areas

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

Cite this

HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality. / Serrano-Villar, Sergio; Sainz, Talia; Lee, Sulggi A.; Hunt, Peter W.; Sinclair, Elizabeth; Shacklett, Barbara; Ferre, April L.; Hayes, Timothy L.; Somsouk, Ma; Hsue, Priscilla Y.; Van Natta, Mark L.; Meinert, Curtis L.; Lederman, Michael M.; Hatano, Hiroyu; Jain, Vivek; Huang, Yong; Hecht, Frederick M.; Martin, Jeffrey N.; McCune, Joseph M.; Moreno, Santiago; Deeks, Steven G.

In: PLoS Pathogens, Vol. 10, No. 5, e1004078, 2014.

Research output: Contribution to journalArticle

Serrano-Villar, S, Sainz, T, Lee, SA, Hunt, PW, Sinclair, E, Shacklett, B, Ferre, AL, Hayes, TL, Somsouk, M, Hsue, PY, Van Natta, ML, Meinert, CL, Lederman, MM, Hatano, H, Jain, V, Huang, Y, Hecht, FM, Martin, JN, McCune, JM, Moreno, S & Deeks, SG 2014, 'HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality', PLoS Pathogens, vol. 10, no. 5, e1004078. https://doi.org/10.1371/journal.ppat.1004078
Serrano-Villar, Sergio ; Sainz, Talia ; Lee, Sulggi A. ; Hunt, Peter W. ; Sinclair, Elizabeth ; Shacklett, Barbara ; Ferre, April L. ; Hayes, Timothy L. ; Somsouk, Ma ; Hsue, Priscilla Y. ; Van Natta, Mark L. ; Meinert, Curtis L. ; Lederman, Michael M. ; Hatano, Hiroyu ; Jain, Vivek ; Huang, Yong ; Hecht, Frederick M. ; Martin, Jeffrey N. ; McCune, Joseph M. ; Moreno, Santiago ; Deeks, Steven G. / HIV-Infected Individuals with Low CD4/CD8 Ratio despite Effective Antiretroviral Therapy Exhibit Altered T Cell Subsets, Heightened CD8+ T Cell Activation, and Increased Risk of Non-AIDS Morbidity and Mortality. In: PLoS Pathogens. 2014 ; Vol. 10, No. 5.
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abstract = "A low CD4/CD8 ratio in elderly HIV-uninfected adults is associated with increased morbidity and mortality. A subset of HIV-infected adults receiving effective antiretroviral therapy (ART) fails to normalize this ratio, even after they achieve normal CD4+ T cell counts. The immunologic and clinical characteristics of this clinical phenotype remain undefined. Using data from four distinct clinical cohorts and three clinical trials, we show that a low CD4/CD8 ratio in HIV-infected adults during otherwise effective ART (after CD4 count recovery above 500 cells/mm3) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from na{\"i}ve toward terminally differentiated CD8+ T cells, higher levels of CD8+ T cell activation (HLADR+CD38+) and senescence (CD28- and CD57+CD28-), and higher kynurenine/tryptophan ratio. Changes in the peripheral CD4/CD8 ratio are also reflective of changes in gut mucosa, but not in lymph nodes. In a longitudinal study, individuals who initiated ART within six months of infection had greater CD4/CD8 ratio increase compared to later initiators (>2 years). After controlling for age, gender, ART duration, nadir and CD4 count, the CD4/CD8 ratio predicted increased risk of morbidity and mortality. Hence, a persistently low CD4/CD8 ratio during otherwise effective ART is associated with increased innate and adaptive immune activation, an immunosenescent phenotype, and higher risk of morbidity/mortality. This ratio may prove useful in monitoring response to ART and could identify a unique subset of individuals needed of novel therapeutic interventions.",
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AU - Serrano-Villar, Sergio

AU - Sainz, Talia

AU - Lee, Sulggi A.

AU - Hunt, Peter W.

AU - Sinclair, Elizabeth

AU - Shacklett, Barbara

AU - Ferre, April L.

AU - Hayes, Timothy L.

AU - Somsouk, Ma

AU - Hsue, Priscilla Y.

AU - Van Natta, Mark L.

AU - Meinert, Curtis L.

AU - Lederman, Michael M.

AU - Hatano, Hiroyu

AU - Jain, Vivek

AU - Huang, Yong

AU - Hecht, Frederick M.

AU - Martin, Jeffrey N.

AU - McCune, Joseph M.

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AU - Deeks, Steven G.

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