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.
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.
Department of Infectious Diseases, University Hospital Ramón y Cajal, Madrid, Spain.
Sergio
S
Serrano-Villar
Molecular Immune Biology Laboratory, University Hospital Gregorio Marañón, Madrid, Spain.
Talia
T
Sainz
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Sulggi A
SA
Lee
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Peter W
PW
Hunt
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Elizabeth
E
Sinclair
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
Barbara L
BL
Shacklett
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
April L
AL
Ferre
Department of Medical Microbiology and Immunology, School of Medicine, University of California Davis, Davis, California, United States of America.
Timothy L
TL
Hayes
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Ma
M
Somsouk
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Priscilla Y
PY
Hsue
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Mark L
ML
Van Natta
Department of Epidemiology, Johns Hopkins University, Baltimore, Maryland, United States of America.
Curtis L
CL
Meinert
Case Western Reserve University, Cleveland, Ohio, United States of America.
Michael M
MM
Lederman
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Hiroyu
H
Hatano
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Vivek
V
Jain
Bioengineering and Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
Yong
Y
Huang
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Frederick M
FM
Hecht
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, United States of America.
Jeffrey N
JN
Martin
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Joseph M
JM
McCune
Department of Infectious Diseases, University Hospital Ramón y Cajal, Madrid, Spain.
Santiago
S
Moreno
Department of Medicine, University of California San Francisco, San Francisco, California, United States of America.
Steven G
SG
Deeks
D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000188:drug therapy* / Q000453:epidemiology* / Q000276:immunology; D015497:HIV-1; D006801:Humans; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D009017:Morbidity; D009026:Mortality; D012307:Risk Factors; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology*; D016896:Treatment Outcome
D019380:Anti-HIV Agents