Although the effect of highly active antiretroviral therapy (HAART) on HIV-1 replication has been established, the mechanisms involved in restoration of immune responses and reconstitution remain unknown. This study provides evidence of changes in expression of type 1 and type 2 cytokine-specific mRNA occurring during HIV-1 infection, before and after initiation of HAART. Unstimulated PBMCs from nine HIV-1-infected individuals obtained at different time intervals before and after the initiation of HAART were assessed for specific IFN-gamma, IL-2, IL-4, and IL-10 mRNA expression, using RT-PCR. Correlation with CD4+ T cell counts and viral load was also carried out. Before initiation of HAART, in all patients, little expression of specific IFN-gamma and IL-2 (type 1 cytokine) mRNA was noted. In contrast, expression of specific IL-4 and/or IL-10 (type 2) mRNA was readily detectable in the majority of patients. After initiation of HAART there was a continuous increase in IFN-gamma and IL-2 mRNA expression, although the latter occurred in lower amounts. This paralleled a dramatic reduction in viral load and increase in CD4+ T cell counts. Type 2 cytokine-specific mRNA expression fell to undetectable levels and in some cases reappeared later in the course of HAART. Predominant expression of type 2 cytokine mRNA, before initiation of HAART, concurs with previous findings of a dominant antiproliferative, type 2 cytokine profile during HIV-1 infection. Reversion of the cytokine profile, after HAART, to a strong type 1 profile suggests that in addition to suppressing virus replication directly the immune system may be given a chance to recover.