Journal
PLOS PATHOGENS
Volume 10, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.1004078
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Categories
Funding
- National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health [K24 AI069994, PO1 AI071713, R56 AI100765, R21 AI087035, R21 AI078774, RO1 AI087145, P01AI076174]
- NIMH [R01 MH54907]
- Doris Duke Charitable Foundation [2008047]
- UCSF/Gladstone Institute of Virology & Immunology CFAR [P30 AI027763]
- UCSF Clinical and Translational Research Institute Clinical Research Center [UL1 RR024131]
- Delaney AIDS Research Enterprise (DARE) [NIAID U19 AI0961090]
- Center for AIDS Prevention Studies [P30 MH62246]
- CFAR Network of Integrated Systems [R24 AI067039]
- amfAR
- Spanish Ministry of Health and Innovation
- Spanish Society of Internal Medicine of Madrid-Castilla La Mancha
- Spanish AIDS Research Network (RIS)
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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/mm(3)) is associated with a number of immunological abnormalities, including a skewed T cell phenotype from naive 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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