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 L. 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

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
  • Medicine(all)

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 L.; 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, BL, 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 L. ; 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 L.

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.

AU - Moreno, Santiago

AU - Deeks, Steven G.

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