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

• Published in: PLoS pathogens 2014-05, Vol.10 (5), p.e1004078-e1004078
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; Adult; AIDS; Anti-HIV Agents - therapeutic use; Antiretroviral drugs; Antiretroviral Therapy, Highly Active; Biology and life sciences; California; Case-Control Studies; CD4-CD8 Ratio; CD8-Positive T-Lymphocytes - immunology; Cohort Studies; Drug therapy; Female; Health aspects; Highly active antiretroviral therapy; HIV; HIV infection; HIV Infections - drug therapy; HIV Infections - epidemiology; HIV Infections - immunology; HIV-1; Human immunodeficiency virus; Humans; Lymphocyte Activation; Lymphocyte Count; Male; Medicine and health sciences; Morbidity; Mortality; Patient outcomes; Risk Factors; Spain; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - pathology; Treatment Outcome
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1004078

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.