CD4+ T-Lymphocyte Nadir and the Effect of Highly Active Antiretroviral Therapy on Phenotypic and Functional Immune Restoration in HIV-1 Infection

To evaluate the effects of the timing of highly active antiretroviral therapy (HAART) on immune reconstitution, we compared lymphocyte subpopulations and lymphocyte proliferation (LP) in response to Candida albicans, cytomegalovirus, HIV p24, Mycobacterium avium complex, pokeweed mitogen, streptokinase, and tetanus toxoid in 43 patients with pretherapy advanced, moderately advanced, and early chronic HIV-1 infection. All patients had recent CD4+ T-cell counts >450/μl and HIV RNA <400 copies/ml for >12 months. CD4+ nadirs were positively correlated with recent numbers of CD4+ T-cells (P < 0.001), memory cells (P < 0.001), and naı&#x0308;ve CD4+ T-cells (P < 0.05) and CD4+ CD28+ T-lymphocytes (P < 0.05) and were negatively correlated with recent CD8+ T-lymphocyte counts (P < 0.05). Only CD4+ naı&#x0308;ve T-cells normalized when HAART was initiated at lower CD4+ T-cell levels. Fifty-three percent of patients had LP responses to HIV p24 antigen. While LP responses to prevalent antigens were usually present, responses to tetanus toxoid were more common with higher CD4+ T-lymphocyte nadirs (P < 0.05). Delaying HAART may limit phenotypic and functional immune restoration in HIV-1 infection.