BASIC SCIENCE Differential Upregulation of CD38 on Different T-Cell Subsets May Influence the Ability to Reconstitute CD4 + T Cells Under Successful Highly Active Antiretroviral Therapy Jose ´ Miguel Benito, MD, PhD,* Mariola Lo ´pez, MsC,* Sara Lozano,* Celia Ballesteros,* Pilar Martinez, MD,† Juan Gonza ´lez-Lahoz, MD,* and Vincent Soriano, MD, PhD* Background: Immune activation is an independent surrogate marker of CD4 T-cell depletion in HIV-infected patients. Highly active antiretroviral therapy (HAART) reduces disease progression as a direct consequence of suppressing HIV replication. Immune func- tion does not normalize completely in most subjects on HAART, however, perhaps reflecting residual HIV replication. So far, it is unclear to what extent immune activation may influence the evolution of CD4 T-cell counts in patients on HAART. Patients and Methods: The expression of CD38 on naive and memory subsets of CD4 + and CD8 + T cells was measured quan- titatively by flow cytometry in 62 drug-naive HIV-positive and 30 HIV-uninfected controls. In addition, the evolution of this marker as well as that of some virologic parameters (plasma viremia and pro- viral load) and CD4 counts were assessed in 25 HIV-infected individuals who initiated HAART and were followed for 12 months. Results: The mean level of CD38 on memory CD4 + and CD8 + T cells as well as in naive CD8 + cells was significantly higher in drug- naive HIV-positive subjects than in HIV-negative controls. Moreover, it was highly correlated with viral load titers. In patients on successful HAART, immune activation declined in all T-cell subsets, particularly among memory CD8 + cells. It remained elevated with respect to HIV- negative controls, however, even after 12 months of HAART. There was a significant correlation between the CD8 + T-cell activation decay and the increase of CD4 + T cells on HAART. Patients with the highest decline in CD8 activation were those showing the highest CD4 T-cell gains after 12 months of therapy. Conclusions: The level of CD38 expression on different T-cell subsets is differentially upregulated in drug-naive HIV-infected patients. After successful HAART, immune activation decreases in all T-cell subsets, although it still remains elevated in most cases after 12 months of HAART. The extent of immune deactivation under successful HAART correlates with the ability to reconstitute CD4 counts. Key Words: HIV, CD38, immune activation, highly active anti- retroviral therapy (J Acquir Immune Defic Syndr 2005;38:373–381) T he activation of the immune system is one of the principal mechanisms of HIV pathogenesis. Activation of T lym- phocytes results in increased levels of proliferation and apo- ptosis 1,2 and is thought to be one of the main mechanisms of CD4 + T-cell depletion in untreated HIV-infected individuals. T-cell activation is accompanied by an elevated expression of different antigens on the surface of T lymphocytes. The expression of CD38 on CD8 + T cells has been looked at with particular attention in recent years. 3–5 It is already elevated during the first stages of HIV infection, and it steadily goes up with disease progression. 5 The upregulation of CD38 on CD8 + T cells most likely reflects dynamic interactions between HIV and the immune response. Different studies conducted during the late 1990s assessed the prognostic value of CD38 as a marker of disease progression. Many found CD38 on CD8 + cells to be a surrogate marker for disease progression, independent of the CD4 count and plasma viremia. 4,6–8 Occasionally, the level of CD8 + CD38 + cells was even more predictive of disease progression than the CD4 count and/or plasma viremia. 7,9–11 Moreover, high levels of CD8 + CD38 + T cells are also highly predictive of subsequent CD4 + T-cell declines. 12,13 Finally, a recent report has concluded that activation of CD8 + T cells rather than plasma viremia pre- dicts CD4 + T-cell loss. 14 The prognostic value of CD38 expression on CD8 + T cells may be further improved by evaluating CD38 expression on CD8 + CD45RO + cells. 12 This is supported by the fact that CD8 + CD45RA + T cells constitutively express low levels of CD38 even in HIV-uninfected controls 5 and thus add some confounding background noise. The prognostic value of CD38 assessment may be further improved by evaluating the mean intensity of this antigen rather than just the proportion of positive cells. 15 Because the CD38 antigen is expressed in a continuous fashion, it seems more appropriate to analyze it quantitatively. This approach may avoid mistakes derived from the subjective variability of cursor placement when scoring positive cells. Received for publication August 3, 2004; accepted December 1, 2004. From the *Service of Infectious Diseases, Hospital Carlos III, Madrid, Spain; and †Hematology Unit, Hospital Carlos III, Madrid, Spain. Reprints: Jose ´ Miguel Benito, Service of Infectious Diseases, Hospital Carlos III, Madrid 28029, Spain (e-mail: jbenito1@hotmail.com). Copyright Ó 2005 by Lippincott Williams & Wilkins J Acquir Immune Defic Syndr  Volume 38, Number 4, April 1 2005 373