Since posting recently about studies investigating the relevance of the CD4/CD8 ratio in the antiretroviral therapy era, several new papers and presentations have provided more information on the topic. Last week in the open access journal PLoS Pathogens, Sergio Serrano-Villar and colleagues reported evidence that a low CD4/CD8 ratio (less than or equal to 0.4)—despite CD4 T cell recovery to a count above 500 on ART—is associated with low naïve CD8 T cells, elevated levels of activated and senescent CD8 T cells, increased innate immune activation, and a greater risk of non-AIDS events. After controlling for age, gender, ART duration and both nadir and proximal CD4 count, each 10% decrease in the CD4/CD8 ratio was associated with 48% higher odds of serious non-AIDS events. In a separate cohort that started ART with advanced disease, a significant correlation between the CD4/CD8 ratio and the risk of mortality was documented. In this analysis, the researchers report that for each 10% increase in the CD4/CD8 ratio on ART there was a 15% decrease in the risk of death. Individuals initiating ART earlier in the course of HIV infection exhibited greater and more rapid improvements in the CD4/CD8 ratio compared to those starting late.
A poster at CROI 2014 presented similar findings. Cristina Mussini and colleagues assessed whether the CD4/CD8 ratio predicted clinical progression in the Icona cohort in Italy. The CD4/CD8 ratio was a significant predictor of the risk of serious non-AIDS events and death, independent of CD4 T cell counts. Normalization of the CD4/CD8 ratio (to greater than or equal to 1) only occurred in a minority of participants, and was more common among younger individuals, those with higher CD4/CD8 ratios at ART initiation, and those starting ART in more recent periods at higher CD4 T cell counts. Another poster at CROI from Talia Sainz et al described the role of CMV infection in lowering CD4/CD8 ratios in HIV-positive people, as is also known to occur in the HIV-negative elderly. Lastly, a recent paper in PLoS One published by Willard Tinago and colleagues from the laboratory of Paddy Mallon in Dublin looked at the links between the CD4/CD8 ratio and other immunological perturbations, with results that appear consistent with those reported by Sergio Serrano-Villar’s group.
The discussion section of the Serrano-Villar paper notes that the data imply that the CD4/CD8 ratio could be useful for monitoring responses to therapies that aim to reduce residual immune activation. Additionally, HIV-positive individuals on suppressive ART who do not experience an increase in the CD4/CD8 ratio “might benefit from screening programs or aggressive management of concomitant risk factors for aging-associated disease.”
PLoS Pathog. 2014 May 15;10(5):e1004078. doi: 10.1371/journal.ppat.1004078. eCollection 2014.
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.
Serrano-Villar S, Sainz T, Lee SA, Hunt PW, Sinclair E, Shacklett BL, Ferre AL, Hayes TL, Somsouk M, Hsue PY, Van Natta ML, Meinert CL, Lederman MM, Hatano H, Jain V, Huang Y, Hecht FM, Martin JN, McCune JM, Moreno S, Deeks SG.
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.
Cristina Mussini et al. Incidence of CD4/CD8 Ratio Normalization and Its Role in the Onset of Non-AIDS-Related Events. Abstract #753, Conference on Retroviruses and Opportunistic Infections, March 3-6 2014, Boston, MA
Talia Sainz et al. CMV and HIV: A Double Hit On the CD4/CD8 Ratio. Abstract #243, Conference on Retroviruses and Opportunistic Infections, March 3-6 2014, Boston, MA
PLoS One. 2014 May 9;9(5):e97011. doi: 10.1371/journal.pone.0097011. eCollection 2014.
Tinago W, Coghlan E, Macken A, McAndrews J, Doak B, Prior-Fuller C, Lambert JS, Sheehan GJ, Mallon PW; Mater Immunology Study Group.
BACKGROUND: Although effective antiretroviral therapy(ART) increases CD4+ T-cell count, responses to ART vary considerably and only a minority of patients normalise their CD4+/CD8+ ratio. Although retention of naïve CD4+ T-cells is thought to predict better immune responses, relationships between CD4+ and CD8+ T-cell subsets and CD4+/CD8+ ratio have not been well described.
METHODS: A cross-sectional study in a cohort of ambulatory HIV+ patients. We used flow cytometry on fresh blood to determine expanded CD4+ and CD8+ T-cell subsets; CD45RO+CD62L+(central memory), CD45RO+CD62L-(effector memory) and CD45RO-CD62L+(naïve) alongside routine T-cell subsets(absolute, percentage CD4+ and CD8+ counts), HIVRNA and collected demographic and treatment data. Relationship between CD4+/CD8+ T-cell ratio and expanded T-cell subsets was determined using linear regression analysis. Results are median[IQR] and regression coefficients unless stated.
RESULTS: We recruited 190 subjects, age 42(36-48) years, 65% male, 65.3% Caucasian, 91% on ART(52.6% on protease inhibitors), 78.4% with HIVRNA<40cps/ml and median ART duration 6.8(2.6-10.2) years. Nadir and current CD4+ counts were 200(112-309) and 465(335-607) cells/mm3 respectively. Median CD4+/CD8+ ratio was 0.6(0.4-1.0), with 26.3% of subjects achieving CD4+/CD8+ ratio>1. Of the expanded CD4+ T-cell subsets, 27.3(18.0-38.3)% were naïve, 36.8(29.0-40.0)% central memory and 27.4(20.0-38.5)% effector memory. Of the CD8+ T-cells subsets, 16.5(10.2-25.5)% were naïve, 19.9(12.7-26.6)% central memory and 41.0(31.8-52.5)% effector memory. In the multivariable adjusted analysis, total cumulative-ART exposure(+0.15,p = 0.007), higher nadir CD4+ count(+0.011,p<0.001) and higher %CD8+ naive T-cells(+0.0085,p<0.001) were associated with higher CD4+/CD8+ ratio, higher absolute CD8+ T-cell(-0.0044,p<0.001) and higher %CD4+ effector memory T-cells(-0.004,p = 0.0036) were associated with lower CD4+/CD8+ ratio. Those with CD4+/CD8+ ratio>1 had significantly higher median %CD8+ naive T-cells; 25.4(14.0-36.0)% versus 14.4(9.4-21.6)%, p<0.0001, but significantly lower absolute CD8+ count; 464(384.5-567) versus 765(603-1084) cells/mm3, p<0.001.
CONCLUSIONS: Study suggests important role for naïve CD8+ T-cell populations in normalisation of the immune response to HIV-infection. How these findings relate to persistent immune activation on ART requires further study.