Although undesirable, immune reconstitution syndrome (IRS) indicates a favourable effect of HAART and it should be differentiated from an opportunistic infection because of their distinct implications and management. Our group analysed different immunological parameters with the aim of identifying IRS predictors in patients who begin HAART. We found that CD8+CD25+ cell pretreatment values in patients who developed IRS were four times higher than in those patients who did not develop IRS.
aDepartment of Immunology, Fundación Jimenez Díaz-Capio, Madrid, Spain
bDepartment of Infectious Diseases, Fundación Jimenez Díaz-Capio, Madrid, Spain.
Received 3 August, 2007
Revised 9 August, 2007
Accepted 13 August, 2007
In most HIV-positive patients on HAART a decrease in the viral load as well as an increase in the CD4 cell count is observed, resulting in minor morbidity and mortality. After a brief period after starting antiretroviral treatment, from days to months, patients may develop an important inflammatory reaction in spite of an adequate response to therapy. Immune reconstitution syndrome (IRS) could be defined as the presentation or clinical deterioration produced by opportunistic infections in patients with HIV, as a direct result of the increase in immune response to those pathogens during antiretroviral treatment. This syndrome can present in a variable percentage of patients (10–25%) in the 2–3 months after starting HAART , and may generate life-threatening clinical complications. It has been observed that patients beginning HAART with CD4 T-cell counts below 50–100 cells/μl may be specially affected by IRS . Little is known about valid predictors to identify such patients with confidence at the beginning of HAART.
To evaluate this topic, our group analysed different immunological parameters with the aim of identifying IRS predictors in patients beginning HAART.
We evaluated 50 HIV-positive patients, naive or without treatment in the previous year at the beginning of the study, with CD4 T-cell counts less than 100 cells/μl and HIV-1-RNA viral loads greater than 4.5 log.
The increase in the CD4 cell count in the group of patients without IRS, between months 0 and 6, was 4.6 times its basal value, whereas the CD4 cell count increase in the group of patients with IRS, between months 0 and 6, was eight times its basal value.
The decrease in viral load in the group of patients without IRS, between months 0 and 6, was 70% from basal value, whereas the decrease in viral loads in the group of patients with IRS, between months 0 and 6, was 90% from the basal value.
The rise in the CD4 cell count in patients under HAART is produced in two phases The initial increase in CD4 cells is very rapid and is usually observed in the first 3–6 months after the initiation of HAART. This increase is caused by a rise in memory CD4 cells trapped in the lymphoid tissue and a reduction in T-cell activation. In our study, patients without IRS presented with a progressive increase in values of memory cells, CD4+CD45RO+, but it was not statistically significant from initial values. On the other hand, in the group with IRS we did not find an increase in CD4+CD45RO+, which remained within the same values during the study period.
The evaluation of a regulatory subset, such as CD4+CD25+ and CD8+CD25+, were also considered in both groups (Fig. 1). No differences were found in the evolution of CD4+CD25+ between both groups, in pretreatment values (P = 0.6), nor in the evolution with HAART. With regard to CD8+CD25+ cells, however, pretreatment values in patients who developed IRS were four times higher than pretreatment values in those without IRS (IRS 17 ± 32% versus without IRS 4 ± 6.8%, P = 0.07), such differences being marginally significant.
On the other hand, by analysing the evolution of CD8+CD25+ cells, we found that in patients with IRS, CD8+CD25+ cells decreased fourfold from the basal value by the first month of treatment and remained stable. In the group of patients without IRS, no significant decrease in CD8+CD25+ was found. To our knowledge, no studies have so far described these findings regarding the evolution of CD8+CD25+ in HIV-positive patients with IRS. Data from recent studies showed that, in murine and human models of regulatory T cells, the CD8+CD25+ and CD4+CD25+ cells share similar characteristics. Both CD4+CD25+ and CD8+CD25+ constitutively express Foxp3 and GITR messenger RNA, in the surface proteins CCR8, TNFR2, and the cytoplasmatic protein, cytotoxic T-lymphocyte antigen 4 (CTLA-4) . Similar to CD4+CD25+ cells, CD8+CD25+ cells exert strong suppressive activity on T helper type 1 cells, but much less on T helper type 2 cells . It is known that activated CD8+CD25+ cells do not produce cytokines, but express surface transforming growth factor beta 1 and CTLA-4. The suppressive effect of CD8+CD25+ cells is mediated by the inhibition of responsiveness of target T cells to express the α chain of the IL-2 receptor (IL-2Rα) induced through a combined action of the surface molecules CTLA-4 and transforming growth factor beta 1 .
As the role of CD8+CD25+ cells continues to be unclear, prospective studies will be necessary to evaluate this cell population in HIV-infected patients who begin antiretroviral treatment, to integrate this finding and its real meaning in patients who develop IRS.
1. Ratnam I, Chiu C, Kandala NB, Easterbrook PJ. Incidence and risk factors for immune reconstitution inflammatory syndrome in an ethnically diverse HIV type 1-infected cohort. Clin Infect Dis 2006; 42:418–427.
2. French MA, Lenzo N, John M, Mallal SA, McKinnon EJ, James IR, et al
. Immune restoration disease after the treatment of immunodeficient HIV-infected patients with highly active antiretroviral therapy. HIV Med 2000; 1:107–115.
3. Maggi E, Cosmi L, Liotta F, Romagnani P, Romagnani S, Annunziato F. Thymic regulatory T cells. Autoimmun Rev 2005; 4:579–586.
4. Cosme L, Liotta F, Angeli R, Mazzinghi B, Santarlasci V, Manetti R, et al
. Th2 cells are less susceptible than Th1 cells to the suppresive activity of CD25+ regulatory thymocytes because of their responsiveness to different cytokines. Blood 2004; 103:3117–3121.
© 2007 Lippincott Williams & Wilkins, Inc.
5. Cosmi L, Liotta F, Lazzeri E, Francalanci M, Angeli R, Mazzinghl B, et al
. Human CD8+
thymocytes share phenotypic and functional features with CD4+
regulatory thymocytes. Blood 2003; 112:4107–4114.