Antiretroviral therapy initiation during primary HIV infection enhances both CD127 expression and the proliferative capacity of HIV-specific CD8+ T cells.

OBJECTIVES: HIV-specific CD8+ T cells from patients with primary HIV infection (PHI) and after antiretroviral therapy initiation were evaluated for CD127 expression and proliferative capacity and were compared with cells from chronically-infected patients, including long-term nonprogressors and HIV controllers. METHODS: We studied 30 patients with PHI (from the Agence Nationale de Recherche sur le SIDA Primo-infection Cohort) and 33 patients with chronic HIV infection (including nonprogressor patients from the Agence Nationale de Recherche sur le SIDA ALT Cohort and the Agence Nationale de Recherche sur le SIDA HIV Controllers Study Group). HIV-specific CD8+ T cells were identified by costaining with HIV human leukocyte antigen class I pentamers. CD127 expression was assessed by flow cytometry and cell proliferation by carboxyfluorescein succinimidyl ester labeling. RESULTS: During PHI, most HIV-specific CD8+ T cells coexpressed CD27 and CD45RO, were highly activated, and showed weak Bcl-2 expression. Their CD127 expression was very low and correlated negatively both with HIV RNA and DNA levels and with expression of the activation marker CD38. CD127 expression correlated positively with CD4 cell count, Bcl-2 expression and proliferative capacity. Strong CD127 expression was observed in the two groups of chronically-infected nonprogressors. CD127 expression on HIV-specific CD8+ T cells increased in early-treated PHI patients, reaching levels similar to those observed in nonprogressors. In parallel, these cells acquired strong proliferative capacity. No change in CD127 expression or proliferative potential was observed in untreated patients. CONCLUSION: Early antiretroviral therapy initiation enhances CD127 expression on HIV-specific CD8+ T cells, reaching levels similar to those observed in aviremic nonprogressors, and restores their proliferative capacity.

Modulation of interleukin-7 receptor expression characterizes differentiation of CD8 T cells specific for HIV, EBV and CMV.

OBJECTIVES: To further understand differentiation and homeostasis of CD8 T cells specific for HIV, Epstein-Barr Virus (EBV) and cytomegalovirus (CMV) during HIV infection, we investigated interleukin-7 receptor alpha (IL-7Ralpha) expression on those virus-specific T cells. METHODS: Microarrays and cytometry analyses were performed on peripheral blood mononuclear cells (PBMC), total and tetramer-binding virus-specific CD8 T cells from 66 HIV-infected patients. RESULTS: Microarray analysis revealed reduced levels of IL-7Ralpha and increased levels of perforin with disease progression in total PBMC. This loss of IL-7Ralpha expression was observed on CD8 T cells and was inversely related to perforin expression. The relative expression of both molecules defined three new subsets: IL-7Ralpha(pos)Perforin(neg); IL-7Ralpha(loneg)Perforin(lo); and IL-7Ralpha(loneg)Perforin(hi) corresponding to naive and effector-memory CD8 differentiation, as assessed by CD45RA/CD11a. The IL-7Ralpha expression decreased along the CD8 differentiation pathway defined by CD27 and CD28. In contrast, IL-7Ralpha expression was down-modulated on all the CD8 T cells specific for HIV, EBV and CMV that were almost exclusively IL-7Ralpha(lo/neg)Perforin(lo) and was parallel with the CD27 expression. In addition, this low IL-7Ralpha expression on HIV-specific CD8 T cells was independent of virus load and T-cell activation and remained stable during the first 6 months of antiretroviral therapy despite successful control of HIV replication. CONCLUSION: The relative expression of IL-7Ralpha, perforin reveals new aspects of virus-specific CD8 T cell differentiation, independently of T-cell activation and virus load. This opens new perspectives for understanding homeostasis of those cells and immune-based therapeutic strategies.

The HIV infection and immune activation: "to fight and burn".

Immune activation, a normal immune reaction to pathogens, is now recognized as a major driving force of the CD4 T-cell depletion and immune disorders caused by HIV. By contrast, the natural hosts of its ancestor virus, simian immunodeficiency virus, have adapted to this virus by blocking immune activation and remaining healthy. This review will focus on evidence demonstrating how immune activation associated with HIV infection exhausts immune defenses to HIV as well as the immune system, thus leading to immunosenescence and immunodeficiency, and how treatment can disrupt this vicious and ultimately fatal circle.

Invasive aspergillosis in allogeneic stem cell transplant recipients: increasing antigenemia is associated with progressive disease.

The kinetics of serum Aspergillus galactomannan, as determined by enzyme-linked immunosorbent assay, was examined in 37 allogeneic stem cell transplant (SCT) recipients treated for invasive aspergillosis (IA). Fifty-eight periods of response ("response episodes") were evaluated. There were 42 response episodes that were considered "treatment failures" and 16 that were considered "good" (that is, complete or partial) responses. At baseline (the first day of each new response episode), the patients who experienced treatment failure and those who had good responses did not differ significantly with regard to median galactomannan index (GMI) value. Thereafter, GMI values significantly increased in the treatment failure group, whereas no significant changes were observed in the good response group (P=.002). An increase in the GMI value of 1.0 over the baseline value during the first week of observation was predictive of treatment failure with a sensitivity of 44%, a specificity of 87%, and a positive predictive value of 94%. We conclude that serial determination of serum GMI values is a useful tool for assessing prognosis of IA in allogeneic SCT recipients during treatment.