An inversion of the normal ratio between CD4 and CD8 T cells was noted in the very first case reports of individuals with AIDS, before HIV was even identified. Although a number of studies subsequently reported an association between the CD4/CD8 ratio and risk of disease progression, CD4 T cell counts were more extensively researched and became the most commonly used surrogate marker of immune system health in HIV-positive people. In recent years, data has emerged from cohort studies of very elderly HIV-negative people indicating that, in this population, the CD4/CD8 ratio is a strong predictor of the risk of aging-associated diseases and mortality. This new information prompted the research group of Sergio Serrano-Villar at the University Hospital Ramón y Cajal in Madrid to evaluate whether measurement of the CD4/CD8 ratio may provide information about the risk of morbidity and mortality in HIV-positive people in the current era of antiretroviral therapy (ART).
Last year, Serrano-Villar and colleagues published preliminary studies showing associations between the CD4/CD8 ratio and levels of immune activation and markers of immune system aging (immunosenescence) in HIV infection. In two new papers published in HIV Medicine and PLoS One, they now extend these findings and report statistically significant associations between the CD4/CD8 ratio and markers of age-associated disease and the clinical outcomes of non-AIDS-related morbidity and mortality in HIV-positive people. The PLoS One study assesses the link between the CD4/CD8 ratio and several dissimilar non-AIDS diseases in people on ART, and reports a significant association in each case. Separate analyses of participants with low CD4 nadirs (<200 cells) and those with good CD4 recovery on ART (to >350 cells) find that CD4/CD8 ratios remain independently associated with non-AIDS events in each subgroup.
In discussing the implications of their findings, the researchers write: “patients with failure to increase the CD4/CD8 ratio despite achieving full immunovirological response to ART might benefit from screening programs and aggressive management of concomitant risk factors for age-associated disease.” They also note that, since there appears to be a relationship between immune activation and the CD4/CD8 ratio, such individuals may be prime candidates for inclusion in clinical trials of interventions that aim to reduce immune activation and associated adverse clinical outcomes. However, several limitations to the study are acknowledged, and the authors stress that: “before using the CD4/CD8 ratio as a surrogate of serious non-AIDS-related illnesses, these results should be reproduced in larger and prospective studies.”
As it currently stands, there are very few reports of therapies capable of improving low CD4/CD8 ratios in HIV-positive people on ART. IL-7 increases both CD4 and CD8 T cell numbers, and according to a new study published in PLoS Pathogens, may reduce markers of inflammation, but the clinical impact of this cytokine has yet to be evaluated. A further complication is that the company behind IL-7, Cytheris, recently went bankrupt, leaving the rights to its development for HIV in the hands of the French Agence Nationale de Recherche sur le SIDA (ANRS) and a small biotech named Cognate Biosciences. SB-728-T, a gene therapy under development by Sangamo Biosciences, has been reported to significantly improve CD4/CD8 ratios in people on ART, but the duration of the effect is unclear and the company appears uninterested in developing the approach for people with suboptimal immune reconstitution (their focus is on attempting to achieve control of HIV replication after ART interruption). The therapy is also complex to administer because it involves the extraction, expansion and genetic modification of CD4 T cells, followed by reinfusion. A letter from TAG and many other community activists and organizations asking the company to continue to study the potential of SB-728-T to promote immune reconstitution fell on deaf ears.
Although not directly connected to the work of Sergio Serrano-Villar and colleagues, another study on the topic of the CD4/CD8 ratio in HIV infection was published online by the Journal of Immunology this past Monday. Marcus Buggert and a Swedish research team used a bioinformatics approach to explore the connections between several of the laboratory measures used to monitor HIV disease progression (including CD4 count and CD4/CD8 ratio) and a large suite of T cell markers that are perturbed by HIV infection (including activation, exhaustion and immunosenescence markers). Focusing primarily on untreated HIV infection, the researchers find that the CD4/CD8 ratio is the best predictor of the combined pathological changes to the T cell immune system that occur in HIV-positive people compared to uninfected controls. The paper concludes: “these findings are of particular interest to future therapy or cure studies, in which simple measurements are required to monitor ongoing pathological events of the T cell repertoire in HIV-infected subjects.”
HIV Med. 2014 Jan;15(1):40-9. doi: 10.1111/hiv.12081. Epub 2013 Sep 6.
Serrano-Villar S, Moreno S, Fuentes-Ferrer M, Sánchez-Marcos C, Avila M, Sainz T, de Villar NG, Fernández-Cruz A, Estrada V.
OBJECTIVES: Inversion of the CD4:CD8 ratio (< 1) has been identified as a hallmark of inmmunosenescence and an independent predictor of mortality in the general population. We aimed to assess the association between the CD4:CD8 ratio and markers of age-associated disease in treated HIV-infected patients with good immunovirological response.
METHODS: A cross-sectional analysis was conducted in 132 HIV-infected adults on antiretroviral therapy (ART), with plasma HIV RNA < 50 HIV-1 RNA copies/mL for at least 1 year, CD4 count > 350 cells/μL and age < 65 years. We analysed the associations between the CD4:CD8 ratio and subclinical atherosclerosis [assessed using carotid intima-media thickness (IMT)], arterial stiffness [assessed using the augmentation index (AIx)], the estimated glomerular filtration rate (eGFR), muscle wasting and sarcopenia [assessed using appendicular lean mass/height(2) (ALM) measured by dual-energy X-ray absorptiometry (DEXA)].
RESULTS: CD4:CD8 ratio inversion was associated with higher IMT, lower eGFR and lower ALM (all values P < 0.05), but not with AIx. In multivariate analyses adjusted for age, sex, hypertriglyceridaemia, tobacco use and cumulative ART exposure, inversion of the CD4:CD8 ratio was independently associated with higher IMT [odds ratio (OR) 2.9; 95% confidence interval (CI) 1.2-7.1], arterial stiffness (OR 4.8; 95% CI 1.0-23.5) and lower eGFR (OR 5.2; 95% CI 1.0-64.4), but not sarcopenia (OR 0.7; 95% CI 0.2-2.7). These associations persisted when models were applied to subjects with nadir CD4 counts > 200 cells/μL and those with CD4 counts > 500 cells/μL.
CONCLUSIONS: The CD4:CD8 ratio in treated HIV-infected subjects with good immunovirological response is independently associated with markers of age-associated disease. Hence, it might be a clinically useful predictor of non-AIDS-defining conditions.
PLoS ONE 9(1): e85798. doi:10.1371/journal.pone.0085798
Sergio Serrano-Villar, María Jesús Pérez-Elías, Fernando Dronda, José Luis Casado, Ana Moreno, Ana Royuela, José Antonio Pérez-Molina, Talia Sainz, Enrique Navas, José Manuel Hermida, Carmen Quereda, Santiago Moreno
Published: January 30, 2014DOI: 10.1371/journal.pone.0085798
A low CD4/CD8 ratio has been identified in the general population as a hallmark of inmmunosenescence and a surrogate of all-cause mortality. We aimed to investigate in treated HIV-infected individuals the relationship between the CD4/CD8 ratio and serious non-AIDS events.
Case-control study within a prospective hospital-based cohort of HIV-infected subjects during at least one year of ART-mediated viral suppression. Cases were patients with serious non-AIDS events (non-AIDS malignancies, cardiovascular disease, and end-stage kidney disease), and controls individuals who did not developed non-AIDS events during follow-up. Data were analyzed using ROC analysis and multivariate logistic regression. Conditional logistic regression was performed in 200 cases/controls matched by age, sex, nadir CD4 and proximal CD4 counts.
We analyzed 407 subjects (109 cases, 298 controls). The CD4/CD8 ratio was lower in cases (0.44 vs. 0.70, P<0.0001), with higher discriminatory ability for the detection of non-AIDS events than the CD4 count, CD8 count and nadir CD4. Multivariate analyses (adjusted for age, sex, nadir CD4, proximal CD4 count, year of ART initiation and ART duration) confirmed the independent association of a low CD4/CD8 ratio with the risk of non-AIDS morbidity (per CD4/CD8 ratio quartile decrease, OR, 2.9; 95% CI, 1.3–6.2) and non-AIDS mortality (OR, 2.8; 95% CI, 1.5–5.3).
The CD4/CD8 ratio provides additional information to the CD4 counts and nadir CD4 in treated HIV-infected individuals, since it is independently associated with the risk of non-AIDS-related morbidity and mortality. This association is robust and maintained within different subgroups of patients.
The Journal of Immunology
Published online before print February 3, 2014, doi: 10.4049/jimmunol.1302596
Marcus Buggert, Juliet Frederiksen, Kajsa Noyan, Jenny Svärd, Babilonia Barqasho, Anders Sönnerborg, Ole Lund, Piotr Nowak, and Annika C. Karlsson
HIV disease progression is characterized by numerous pathological changes of the cellular immune system. Still, the CD4 cell count and viral load represent the laboratory parameters that are most commonly used in the clinic to determine the disease progression. In this study, we conducted an interdisciplinary investigation to determine which laboratory parameters (viral load, CD4 count, CD8 count, CD4 %, CD8 %, CD4/CD8) are most strongly associated with pathological changes of the immune system. Multiparametric flow cytometry was used to assess markers of CD4+ and CD8+ T cell activation (CD38, HLA-DR), exhaustion (PD-1, Tim-3), senescence (CD28, CD57), and memory differentiation (CD45RO, CD27) in a cohort of 47 untreated HIV-infected individuals. Using bioinformatical methods, we identified 139 unique populations, representing the “combined T cell pathogenesis,” which significantly differed between the HIV-infected individuals and healthy control subjects. CD38, HLA-DR, and PD-1 were particularly expressed within these unique T cell populations. The CD4/CD8 ratio was correlated with more pathological T cell populations (n = 10) and had a significantly higher average correlation coefficient than any other laboratory parameters. We also reduced the dimensionalities of the 139-unique populations by Z-transformations and principal component analysis, which still identified the CD4/CD8 ratio as the preeminent surrogate of combined T cell pathogenesis. Importantly, the CD4/CD8 ratio at baseline was shown to be significantly associated with CD4 recovery 2 y after therapy initiation. These results indicate that the CD4/CD8 ratio would be a suitable laboratory predictor in future clinical and therapeutic settings to monitor pathological T cell events in HIV infection.