Editorial Commentary:Immunological Nonresponse to Highly Active Antiretroviral Therapy in HIV‐Infected Subjects: Is the Bone Marrow Impairment Causing CD4 Lymphopenia?

In this issue of Clinical Infectious Diseases, Isgrò et al. [1] demonstrated that HIV-infected patients who were unable to achieve immunological reconstitution despite viral suppression during HAART demonstrated specific defects of bone marrow clonogenic function. In the pre-HAART era, it was already observed that some individuals, after acute HIV infection, developed accelerated CD4 cell depletion and cellular immunity impairment leading to AIDS. Indeed, AIDS patients display various degrees of bone marrow failure, including either monocytopenia affecting platelets, neutrophils, and RBCs or, most often, pancytopenia [2]. Although these hematopoietic defects can be attributed to multiple causes, including intercurrent infections and illegal drug use, many studies have demonstrated that advanced HIV infection has a profound impact on bone marrow functions. Indeed, both multilineage and lineage-restricted hematopoietic progenitors are decreased in the bone marrow of HIV-infected patients [3, 4]. For more than a decade, researchers have debated about the pathophysiology of AIDS-related hematopoietic defects, seeking to determine whether HIV is capable of directly infecting hematopoietic progenitors and stem cells. Despite progenitor CD34+ cells that express the viral receptor CXCR4 (previously named fusin) and its ligand CXCL12/SDF1, conflicting results have been reported concerning the susceptibility of these cells to HIV infection. Analysis of hematopoietic progenitors during HIV infection, both in vitro and in vivo, has shown that these cells remain substantially uninfected [5], suggesting that suppression of hematopoiesis in HIV-infected individuals is probably related to an abnormal stromal microenvironment. In particular, it was shown that support of long-term bone marrow culture is highly dependent on the susceptibility of stromal cells to HIV infection. HIV-infected stromal cells cannot provide the optimal milieu of cytokines, extracellular matrix proteins, and adhesion molecules that is required for growth of hematopoietic colonies. Moreover, infected bone marrow cells secrete large amounts of proinflammatory cytokines, such as TNF-α, which will exert inhibitory activity on hematopoiesis by the induction of apoptosis through the Fas ligand-Fas receptor pathway on the bone marrow progenitor cells [6]. Isgrò et al. have shown that bone marrow cells of patients with unsatisfactory immunological response to HAART secrete high levels of TNF-α and display significant upregulation of Fas ligand and Fas receptor. These findings may account for the decreased number of colony-forming cells and of positive long-term bone marrow culture results in these patients [1]. In contrast, antiretroviral therapy in immunological responders results in rapid recovery of bone marrow hematopoietic functions. This effect is associated with inhibition of proinflammatory cytokine and chemokine release by infected stromal cells [7]. Besides secreting TNF-α, stromal layers derived from bone marrow of immunological nonresponders (INRs) display abnormal morphological characteristics resembling the features observed in bone marrow obtained from HIV-infected patients before the start of antiretroviral treatment. On the basis of the hypothesis that INRs have a broad defect of colony formation by bone marrow cells, one would predict that these patients might also experience anemia and thrombocytopenia. However, INRs do not present any of these specific hematological abnormalities, suggesting that other factors, including HIV infection, concur with CD4 lymphopenia. Many researchers have sought to identify the role of bone marrow failure in HIV-infected patients as the cause of the progressive loss of CD4+ T cells and of the associated functional T cell defects. However, in the complex scenario of advanced HIV infection, it is difficult to determine at which level the lymphocyte homeostasis is perturbed. Many mechanisms have been hypothesized for explaining CD4+ T cell lymphopenia in HIV-infected individuals, including factors affecting peripheral lymphocyte homeostasis or related to abnormal lymphocyte output by the thymus or alteration of early lymphoid progenitors at the level of bone marrow CD34+ precursors. Use of animal models that resemble human HIV infection, such as SCID-human thy/Liv models or simian immunodeficiency virus infection in macaques, has shown that depletion of CD34+ and lineage-committed hematopoietic progenitors occurs several days before thymocyte depletion [8, 9]. These observations suggest that the rapid decrease in thymocyte numbers after viral infection is attributable to the loss of lymphoid cell progenitors. The role of de novo T cell production in the context of HIV infection has been further addressed by measurement of T cell kinetics in HIV-infected patients. By using a deuterium-labelled glucose method, Hellerstein et al. [10] have shown that the half-life of blood T cells is decreased in untreated patients from ∼82 days to ∼23 days, but surprisingly, no improvement in half-life is observed after starting antiretroviral therapy. Conversely, the increase in T cell numbers in the peripheral blood that is observed in HIV-infected patients receiving HAART is, in part, attributable to de novo generation of T lymphocytes from the thymus and secondarily to peripheral expansion and/or redistribution of T cells between the lymphoid and blood compartments. The latter mechanism accounts for the rapid increase of both CD4+ and CD8+ cells, mostly of a memory phenotype (CD45RO+, CD62L−), which is observed shortly after the start of the therapy. Instead, the late phase of T cell level augmentation is characterized by the relative increase of CD4+ T cells of naive phenotype (CD45RA+), bearing the T cell receptor excision circles. It is important to point out that starting antiretroviral therapy results in an augmented thymic output, which will expand the skewed immunological repertoire observed in advanced HIV infection. In INRs, CD4+ T cell depletion cannot be reverted by augmented thymic output, because the reduced clonogenic potential of bone marrow lymphoid progenitors cannot replenish the loss of thymocyte progenitors. As predicted on the basis of this model, INRs display the lowest levels of naive T cells and a predominant memory pattern [11]. Moreover, HIV-infected patients who do not reconstitute a normal T cell repertoire also display increased apoptosis and proliferation markers in circulating CD4 lymphocytes, suggesting that augmented lymphocyte activation contributes to the altered homeostasis of the lymphoid compartment in these subjects. These studies can provide a more thorough understanding of the immunopathogenesis of discordant responses to antiretroviral therapies in HIV-infected individuals, thereby contributing to the identification of alternative therapeutic targets. Several researchers have sought to demonstrate a beneficial effect of treatment with IL-2 in patients with inadequate immune recovery despite effective viral suppression, but the results of these trials were not always concordant [12]. It is likely that the addition of IL-2 might increase CD4 T lymphocyte counts by expanding the activated/memory subset without any effect on the naive fraction of CD4 cells. In contrast, INRs display an increased production of IL-7, both in the peripheral blood and in bone marrow, suggesting that other therapeutic options targeted to circumvent the differentiation arrest of lymphoid progenitors at the bone marrow level will be required for an appropriate treatment of these patients. Financial support. Research Grant Nobel from Fondazione Cariplo (Milan, Italy). Potential conflicts of interest. R.B.: no conflicts.