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Editorial: Developmental regulation of P‐glycoprotein and HIV therapy: spare the thymus but spoil the child?

HIV is a merciless assassin that rapidly and efficiently devastates susceptible cells. Its impact extends beyond the immune system of an infected individual, disrupting families and the very structure of societies. Considering the array of life-threatening, opportunistic infections, malignancies, and other diseases accompanying HIV-induced CD4 T cell lymphocytopenia, it was initially surprising to discover that only a small fraction of peripheral blood CD4 T cells is actually infected, even in individuals with advanced disease. The magnitude of HIV immunopathology during the chronic phase of HIV disease is more readily appreciated by examination of the primary and secondary lymphoid organs. In particular, it is clear that HIV often has a devastating impact on thymic architecture and thymopoiesis, with loss of thymic epithelium, infilitration of the thymic perivascular space by CD8 T cells, and depletion of peripheral blood naı̈ve T cells [1]. During the first few years of life, the thymus plays a major role in populating the lymphoid compartment. Therefore, infants with thymic HIV-1 infection can experience near-collapse of T cell populations and dramatic increases in mortality [2]. In adolescents and adults, the thymus plays much a smaller role in populating the periphery with T cells. These age-related differences in the role of thymus largely explain the differences in the effects of antiviral therapy on reconstitution of peripheral T cells between children and adults. However, paraphrasing Mark Twain, reports of a HIV-induced early demise of the thymus were an exaggeration of the available data. The majority of adolescents and adults with advanced HIV infection and AIDS has radiographically demonstrable thymic tissue [3, 4]. Moreover, within months of effective antiretroviral therapy, thymus-dependent reconstitution of peripheral blood T cell populations occurs in children and to a lesser extent in adults [1, 5]. Intriguingly, improved thymopoiesis, resulting in complete or near-complete reconstitution of peripheral CD4 cells, has been observed, even when suppression of HIV plasma viremia is not achieved or maintained. These so-called discordant responses (immunologic success with virologic failure) have been associated with acquisition of drug-resistance mutations in HIV, especially in the HIV protease [6]. Stoddart et al. [7] found that viral variants with proteaseresistant mutations were less virulent in human thymic organ cultures and human thymus implants in SCID-hu Thy/ Liv mice compared with protease inhibitor-susceptible strains. By contrast, no differences in viral replication were observed when these strains were used to infect PBMCs in vitro. How viral drugresistance mutations diminish the virulence of HIV in thymocytes is still uncertain. A report in this issue of JLB suggests an additional mechanism involved in the impact of antiretroviral agents on HIV in the thymus. Haraguchi et al. [8] compared the antiviral activity of two inhibitors of the HIV protease—indinavir and ritonavir—in mature human PBMCs and thymocytes prepared from fetal thymic tissue or fragments of thymus removed from individuals undergoing corrective cardiac surgery. These in vitro studies demonstrated that inhibition of HIV replication in thymocytes was achieved at substantially lower concentrations of drug than in mature T cells. Reasoning that this might result from more effective intracellular concentrations of the drugs, they examined the activity of P-gp—a member of a broader class of ATP-binding cassette transporter proteins, which reduce the intracellular concentrations of many drugs (including protease inhibitors) by expelling these drugs from the cell. With the use of rhodamine 123 efflux to evaluate P-gp activity and RT-PCR to quantify P-gp mRNA, they demonstrated a correlation between P-gp and both antiviral activity of the protease inhibi-