ABSTRACT
HIV replication can now be effectively suppressed using antiretroviral combination regimens. The search continues, however, for ways to restore the immune response and eliminate reservoirs of latent infection. Interleukin-2 (IL-2) may augment the immune response in HIV-infected persons. This article discusses the rationale for using IL-2 in those with HIV disease and reviews key trials of IL-2 treatment regimens.
Subject(s)
HIV Infections/immunology , Immune System/drug effects , Interleukin-2/therapeutic use , Antiretroviral Therapy, Highly Active , CD4 Lymphocyte Count , Dose-Response Relationship, Drug , HIV Infections/drug therapy , Humans , Immunity/drug effects , Immunotherapy , Interleukin-2/administration & dosage , Interleukin-2/pharmacology , Killer Cells, Natural/drug effects , Killer Cells, Natural/immunology , Receptors, Interleukin-2/drug effects , Receptors, Interleukin-2/immunology , Virus Latency/drug effects , Virus Latency/immunologyABSTRACT
When administered in high doses to HIV positive (HIV+) individuals, interleukin 2 (IL-2) causes extreme toxicity and markedly increases plasma HIV levels. Integration of the information from the structure-activity relationships of the IL-2 receptor interaction, the cellular distribution of the different classes of IL-2 receptors, and the pharmacokinetics of IL-2 provides for the rationale that low IL-2 doses should circumvent toxicity. Therefore, to identify a nontoxic, but effective and safe IL-2 treatment regimen that does not stimulate viral replication, doses of IL-2 from 62,500 to 250,000 IU/m2/day were administered subcutaneously for 6 months to 16 HIV+ individuals with 200-500 CD4+ T cells/mm3. IL-2 was already detectable in the plasma of most HIV+ individuals even before therapy. Peak plasma IL-2 levels were near saturating for high affinity IL-2 receptors in 10 individuals who received the maximum nontoxic dose, which ranged from 187,500 to 250,000 IU/m2/day. During the 6 months of treatment at this dose range, plasma levels of proinflammatory cytokines remained undetectable, and plasma HIV RNA levels did not change significantly. However, delayed type hypersensitivity responses to common recall antigens were markedly augmented, and there were IL-2 dose-dependent increases in circulating Natural Killer cells, eosinophils, monocytes, and CD4+ T cells. Expanded clinical trials of low dose IL-2 are now warranted, especially in combination with effective antivirals to test for the prevention of immunodeficiency and the emergence of drug-resistant mutants and for the eradication of residual virions.
