Elevated levels of CD4+CD7- T cells in HIV infection add to the prognostic value of low CD4 T cell levels and HIV-1-RNA quantification.

Abstract

We recently tested the value of several flow cytometric measurements of immune activation to predict the outcome of HIV-1 disease. Our analysis demonstrated that the increase in the percentages of CD4+CD38 +DR+ T cells provided more independent prognostic information for progression to AIDS than the prognostic value of low CD4 T cell levels and HIV-1-RNA quantification [1]. In an extended immunological analysis, two subsets of CD4 T cells (CD4+CD7− and CD4+CD7−CD57+ T cells) were measured. The markers studied were examined because of previous reports that CD4 cell subsets with a loss of cell surface CD7 cell expression were expanded in HIV disease [2] and were associated with low CD4 cell count rescue during antiretroviral therapy [3]. A cohort of 85 HIV-infected heroin users was followed for a mean period of 37 ± 13 months. Centers for Disease Control and Prevention category A included 48 asymptomatic patients and category B included 37 symptomatic patients without AIDS-defining diseases at entry. A total of 19 out of 85 (22%) HIV-positive patients progressed to clinical AIDS. Three-colour immunophenotyping of peripheral blood lymphocytes was performed by flow cytometry. Stained samples were analysed using a FACScan flow cytometer (Becton Dickinson, San Jose, CA, USA) with lysis II software (Becton Dickinson). Plasma HIV-1-RNA levels were measured by reverse-transcriptase polymerase chain reaction (Ultrasensitive Amplicor HIV Test, Roche Molecular Systems, Branchburg, NJ, USA). The Cox proportional hazards model was used to evaluate the prognostic value for the development of AIDS of the baseline measurements of the immunological markers. The prognostic values for the development of AIDS for each marker as a continuous variable are presented in Table 1. The increased risk of AIDS associated with a single 1% increase in the CD4+CD7− lymphocyte percentage was 12%. Each of the functionally distinct lymphocyte subsets was then split into two groups using the median value as the cut-off. A univariate Cox model with CD4 T lymphocyte subsets modelled as categorical variables showed that the CD4+CD7− cell count (median value 11%) was the variable that retained significant prognostic value for progression to AIDS [relative hazard (RH) 5.22;P = 0.0017, 95% confidence interval (CI) 1.85–14.68]. Using Cox multivariate regression analysis adjusted for both CD4 cells and plasma HIV-1-RNA levels, we found that the increase in the percentage of CD4+CD7– T cells retained additional predictive value (RH 3.81;P = 0.02; 95% CI 1.19–12.17). Spearman correlation between levels of CD4+CD7− and CD4+CD38+HLA-DR+ T cells, CD4+CD7− T cells and the CD4 T cell count were 0.51 (P < 0.0001) and −0.42 (P < 0.0001), respectively.Table 1: Tests for prognostic value of selected CD4 T cell subsets for AIDS development: Cox proportional hazards models. It has been suggested that cellular immune activation itself rather than being merely an association with HIV-RNA levels is an additional contributing factor to subsequent disease progression [4]. For the first time, using a prospective study, we have demonstrated that increased levels of CD4+CD7− T cells have additional prognostic value to the CD4 T cell count and plasma HIV-1-RNA levels. The expansion of CD7-negative T cells has been documented in diseases associated with chronically repeated T cell stimulation [5]. In addition to the induction of HLA-DR, it has been observed that HIV can downregulate the CD7 antigen at the cell surface in chronically infected T cells [6]. Furthermore, expanded CD4+CD7− T cells in HIV-positive patients may be low IL-2 producing cells with low levels of proliferation in response to anti-CD3 and recall antigens [7]. These data suggest that a high level of CD4+CD7− T cells, as previously demonstrated for high levels of CD4+CD38+HLA-DR+ T cells [1], reflects the increasing state of immune dysfunction observed during the progression of HIV infection. These results may contribute to a better understanding of differences in the rates of progression among HIV-positive patients, and to the identification of CD4 cell subsets that may play a pathogenic role in the progression of HIV infection. Javier Carbone Juana Gil José M. Benito Angeles Muñóz-Fernández Eduardo Fernández-Cruz