Cited by 611HIV Research and TreatmentHIV-related health complications and treatmentsHIV/AIDS Research and Interventions

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

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Serrano-Villar, Sergio, Sainz, Talia, Lee, Sulggi A., Hunt, Peter W., Sinclair, Elizabeth, Shacklett, Barbara L., Ferre, April L., Hayes, Timothy L. +13 more·2014·PLoS Pathogens

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.

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  1. [24]Devitt E, Rodríguez JM, Pozniak A (2013) CD4 but not CD4:CD8 ratio recovery after 14 years successful HIV suppression [Abstract 311]. In: Proceedings of the 20th Conference on Retrovirus and Opportunistic Infections; 3–6 March 2013; Atlanta, Georgia, United States. CROI 2013.
  2. [40]Hsue P, Scherzer R, Gilman L, Wu Y, Maka K, et al.. (2012) Maraviroc Intensification on Endothelial Function in Treated HIV Infection [Abstract 123]. In: Proceedings of the 19th Conference on Retroviruses and Opportunistic Infections; 5–8 March 2012; Seattle, Washington, United States. CROI 2012.

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Authors
Serrano-Villar, S., Sainz, T., Lee, S. A., Hunt, P. W., Sinclair, E., Shacklett, B. L., Ferre, A. L., Hayes, T. L., Somsouk, M., Hsue, P. Y., Van Natta, M. L., Meinert, C. L., Lederman, M. M., Hatano, H., Jain, V., Huang, Y., Hecht, F. M., Martin, J. N., McCune, J. M., Moreno, S., & Deeks, S. G.
Affiliations
  • University of California, San Francisco (US)
  • University of California, Davis (US)
  • Johns Hopkins University (US)
  • Case Western Reserve University (US)
  • Hospital Universitario Ramón y Cajal (ES)
Venue
PLoS Pathogens
Published
2014-05-15
Volume
10
Issue
5
Pages
e1004078
ISSN
  • 1553-7366 (ISSN-L)
  • 1553-7374
OpenAlex
W2065148379
Cited by
611
References
60
Citations by year
2026: 35 · 2025: 45 · 2024: 39 · 2023: 44 · 2022: 57 · 2021: 51 · 2020: 73 · 2019: 54 · 2018: 53 · 2017: 44 · 2016: 61 · 2015: 49 · 2014: 6
FWCI
23.70
Type
journal article
Language
en
Open access
Locations
  • PLoS Pathogens (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Doris Duke Charitable Foundation
  • amfAR, The Foundation for AIDS Research
  • Delaney AIDS Research Enterprise
  • National Institutes of Health (UL1TR000004, U19 AI0961090, RR024131, AI027763)
  • University of California, San Francisco (P30AI027763, UL1RR024131)
  • National Institute of Mental Health (MH 54907, R01MH054907, MH62246, P30MH062246)
  • National Eye Institute (U10EY008057)
  • National Cancer Institute (K23CA157929)
  • National Institute of Allergy and Infectious Diseases (P01AI071713, AI087035, R21AI087035, K24AI069994, RO1 AI087145, AI027763, RR024131, U19AI096109, AI067039, AI071713, P01AI076174, AI100765, AI069994, AI087145, U19AI0961090, R21AI078774, R01AI057020, R01AI087145, R56AI100765, R24AI067039, P30AI027763)
  • National Center for Research Resources (UL1RR024131)
  • Center for AIDS Prevention Studies, University of California, San Francisco (P30 MH62246)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Emergency Medicine › HIV-related health complications and treatments
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS Research and Interventions
Keywords
HIV infection, CD4/CD8 ratio, antiretroviral therapy, CD8+ T cell activation, T cell senescence, kynurenine/tryptophan ratio, intestinal mucosa, immunosenescence, mortality, CD4 count recovery, treatment initiation timing, immune activation
MeSH terms
Adult, Female, Humans, Lymphocyte Activation, Male, Morbidity, Mortality, Risk Factors, Cohort Studies, HIV-1, HIV Infections, Case-Control Studies, T-Lymphocyte Subsets, CD4-CD8 Ratio, Treatment Outcome, CD8-Positive T-Lymphocytes, Lymphocyte Count, Anti-HIV Agents, Antiretroviral Therapy, Highly Active

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