Isaac Rosado-Sánchez

Thymic function impacts the peripheral CD4/CD8 ratio of HIV-infected subjects.

Background.  The persistence of an inverted CD4/CD8 ratio has been extensively associated with the increased morbimortality of chronic human immunodeficiency virus (HIV)-infected subjects. Thymic function is crucial for the maintenance of T cell homeostasis. We explored the impact of thymic function on the CD4/CD8 ratio of HIV-infected subjects. Methods.  In a cohort of 53 antiretroviral-naive HIV-infected subjects, the measure of thymic volume, as a representative marker for thymic function, was available at baseline and at 12, 24, and 48 weeks post antiretroviral treatment. Results.  Baseline thymic volume was associated with the CD4/CD8 ratio (&rgr; = 0.413, P = .002), being this association highly dependent on the CD4 T cell levels. In subjects who achieved undetectable viral load after treatment (n = 33), a higher baseline thymic volume was associated with a higher increase in CD4 T cell counts and a decreasing trend in CD8 T cell counts during follow-up. Moreover, the baseline thymic volume was independently associated with the normalization of the CD4/CD8 ratio after 96 weeks of treatment (odds ratio, 95% confidence interval: 1.95 (1.07–3.55); P = .03). Conclusions.  Our data indicate the relevance of the remaining thymic function before the start of treatment to the CD4/CD8 ratio of HIV- infected subjects and, hence, potentially, in their clinical progression.

CCR5+ CD8 T-cell levels and monocyte activation precede the onset of acute coronary syndrome in HIV-infected patients on antiretroviral therapy

Acute coronary syndrome (ACS) is nowadays one of the leading causes of morbid-mortality in HIV-infected population, but innate and adaptive immune mechanisms preceding this event are unknown. In this work we comprehensively and longitudinally observed, by multiparametric flow cytometry and following a case-control design, increased CCR5+CD8+ T-cells levels and monocytes expressing activation and adhesion markers in HIV-infected patients who are going to suffer ACS. In addition, we found direct associations between activated CD8+ T-cells and myeloid cells that were only statistically significant in the group of patients with ACS and in the follow up time point just before the ACS. Our data highlight the important role of CCR5 in the onset of ACS and suggest this receptor as a marker of cardiovascular risk and potential therapeutic target to prevent the development of such non-AIDS-related event in HIV-infected patients.

A lower baseline CD4/CD8 T-cell ratio is independently associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects

ABSTRACT We explored if baseline CD4/CD8 T-cell ratio is associated with immunodiscordant response to antiretroviral therapy in HIV-infected subjects. Comparing immunodiscordant and immunoconcordant subjects matched by pretreatment CD4 counts, we observed a lower pretreatment CD4/CD8 T-cell ratio in immunodiscordant subjects. Furthermore, pretreatment CD4/CD8 T-cell ratio, but not CD4 counts, correlated with the main immunological alterations observed in immunodiscordants, including increased regulatory T-cell (Treg) frequency and T-cell turnover-related markers. Then, in a larger cohort, only baseline CD4/CD8 T-cell ratio was independently associated with immunodiscordance, after adjusting by the viral CXCR4-tropic HIV variants. Our results suggest that the CD4/CD8 T-cell ratio could be an accurate biomarker of the subjacent immunological damage triggering immunodiscordance.

Improved CD4 T-cell profile and inflammatory levels in HIV-infected subjects on maraviroc-containing therapy is associated with better responsiveness to HBV vaccination.

Introduction We previously found that a maraviroc-containing combined antiretroviral therapy (MVC-cART) was associated with a better response to the Hepatitis B Virus (HBV) vaccine in HIV-infected subjects younger than 50 years old. We aimed here to extend our previous analysis including immunological parameters related to inflammation, T-cell and dendritic cell (DC) subsets phenotype and to explore the impact of MVC-cART on these parameters. Methods We analyzed baseline samples of vaccinated subjects under 50 years old (n=41). We characterized CD4 T-cells according to the distribution of their maturational subsets and the expression of activation, senescence and prone-to-apoptosis markers; we also quantified Treg-cells and main DC subsets. Linear regressions were performed to determine the impact of these variables on the magnitude of vaccine response. Binary logistic regressions were explored to analyze the impact of MVC-cART on immunological parameters. Correlations with the time of MVC exposure were also explored. Results MVC-cART remained independently associated with HBV-vaccine responsiveness even after adjusting by immunological variables. The %CD4+CD25hiFoxP3+ki67+ and %pDCs were also independently associated. Moreover, HIV-infected subjects on MVC-containing therapy prior to vaccination showed lower inflammatory levels, activated CD4 T-cells and frequency of Treg cells and higher frequency of recent thymic emigrants. Conclusion Treg-cell levels negatively impacted the HBV-vaccine response, whereas higher pDCs levels and a MVC-cART prior to vaccination were associated with better responsiveness. These factors together with the improved phenotypic CD4 T-cell profile and the lower inflammatory levels found in subjects with a MVC-cART prior HBV vaccination could contribute to their enhanced vaccine response.

HIV-infected subjects with poor CD4 T-cell recovery despite effective therapy express high levels of OX40 and α4β7 on CD4 T-cells prior therapy initiation

Background HIV-infected subjects with suboptimal CD4 restoration despite suppressive combined antiretroviral treatment (cART) (immunodiscordant subjects) have been classically characterized after a variable period of time under cART. Recently, we have reported that an increased frequency of proliferating CD4 T-cells in these subjects is already present before the cART onset. The potential contribution of peripheral compensatory homeostatic proliferation (HP) is yet unknown. We aimed to analyze the expression of HP-related cellular markers on CD4 T-cells of immunodiscordant subjects before cART. Methods We analyzed the expression of OX40 and α4β7 on peripheral CD4 T-cells from immunodiscordant and control subjects (n = 21 each group) before cART initiation, and also on available follow-up samples (after 24 month of suppressive cART). Additionally, we tested the expression of these markers in an in vitro system for the study of human HP processes. Results Immunodiscordant subjects showed increased levels of OX40 and α4β7 on CD4 T-cells before cART initiation. While the cART tended to reduce these levels, immunodiscordant subjects still maintained comparatively higher levels of OX40 and α4β7 after 24 months under suppressive cART. These HP-related markers were upregulated in vitro during the human HP, especially during the fast HP. Conclusion Our results are compatible with exacerbated HP processes in immunodiscordant subjects, already before the cART onset.