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PLoS Pathog. 2014 May 15;10(5):e1004078. doi: 10.1371/journal.ppat.1004078. eCollection 2014 May.

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.

Author information

1
Department of Infectious Diseases, University Hospital Ramón y Cajal, Madrid, Spain.
2
Molecular Immune Biology Laboratory, University Hospital Gregorio Marañón, Madrid, Spain.
3
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
4
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
5
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America.
6
Case Western Reserve University, Cleveland, Ohio, United States of America.
7
Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
8
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.

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.

PMID:
24831517
PMCID:
PMC4022662
DOI:
10.1371/journal.ppat.1004078
[Indexed for MEDLINE]
Free PMC Article
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