Research Article: 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

Date Published: May 15, 2014

Publisher: Public Library of Science

Author(s): Sergio Serrano-Villar, Talia Sainz, Sulggi A. Lee, Peter W. Hunt, Elizabeth Sinclair, Barbara L. Shacklett, April L. Ferre, Timothy L. Hayes, Ma Somsouk, Priscilla Y. Hsue, Mark L. Van Natta, Curtis L. Meinert, Michael M. Lederman, Hiroyu Hatano, Vivek Jain, Yong Huang, Frederick M. Hecht, Jeffrey N. Martin, Joseph M. McCune, Santiago Moreno, Steven G. Deeks, Guido Silvestri.

http://doi.org/10.1371/journal.ppat.1004078

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.

Partial Text

It is now anticipated that HIV-infected adults who have access to modern antiretroviral therapy (ART) should be able to suppress HIV replication indefinitely. Although treatment-mediated increases in the peripheral CD4 count are associated with reduced morbidity and mortality, compared to age-matched individuals without HIV infection, those on ART have a higher risk of morbidity and mortality. This risk is predicted in part by the on therapy CD4 count, although achieving an apparent normal CD4 count may not fully restore health [1]–[5]. Indeed, it has been shown that even those treated patients with CD4+ T cell counts above 500 cells/mm3, a further CD4+ T cell count increase is still associated with a slight benefit in terms of mortality [6]. The decreased life expectancy during ART-mediated viral suppression is largely explained by a higher than expected risk of non-AIDS-morbidity, a term that entails a group of conditions generally associated with aging, including cardiovascular, renal, liver, neurologic, and bone disease, as well as cancer [4], [7], [8].

Combining the data from four clinical cohorts and two clinical trials, we demonstrate here that a substantial subset of ART-suppressed HIV-infected adults who have achieved virologic suppression and a normalized peripheral CD4 count (≥500 cells/mm3) have persistently elevated CD8 counts and a low CD4/CD8 ratio. This ratio is correlated with markers of T cell activation and innate immune activation (IDO induction) and with the presence of a previously described immunosenescent phenotype (i.e., low naïve T cell frequencies and increased frequency of terminally differentiated). This imbalance in T cell homeostasis measured in blood is also present in GALT, and the CD4/CD8 ratio shows lower intra-individual variability than the CD4+ or CD8+ T cell counts. Although early ART (<6 month after HIV infection) is associated with more rapid normalization of the CD4/CD8 ratio, an abnormal ratio persists even in these aggressively treated individuals. Among well-treated individuals with high CD4 count, a low ratio was an independent predictor of serious non-AIDS events and mortality. Collectively, these results suggest that a persistently low CD4/CD8 ratio during ART may be a marker of persistent immune dysfunction and inflammation, and that monitoring of this ratio—which can be readily done in most clinics with current assays—may be clinically useful. A truly successful response to ART may require both normalization of the peripheral CD4 count and the CD4/CD8 ratio.   Source: http://doi.org/10.1371/journal.ppat.1004078

 

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