Failure to Reconstitute CD4+ T-Cells Despite Suppression of HIV Replication under HAART

HAART in HIV-1-infected individuals has a broad spectrum of clinical outcomes. In the majority ofpatients, plasma viral load becomes undetectable and CD4+ T-cells increase over time. However, ina number of subjects a discrepancy between plasma viral load and the CD4+ T-cell recovery is observed.CD4+ T-cell count can rise despite persistently detectable plasma viral load (virologic nonresponders),or conversely does not increase despite full plasma viral load suppression (immunologicnonresponder).Defective immune reconstitution may depend on several factors including previous therapeutic failure,duration of antiretroviral therapy, low CD4+ T-cell count at the initiation of HAART, advanced stageof disease, low adherence to HAART, and previous treatment interruption. There is no definitive evidencethat age, viral strain/clade, or host genetic factors play a role in these different responses toHAART. The roles of T-cell subsets, thymic function, and cytokines have been investigated. The increasedT-cell activation/apoptosis has been associated with a lack of effective immunologic response.Unabated virologic replication in lymphoid tissues, despite undetectable plasma viral load,has been proposed as the underlying mechanism of cellular activation. However, this “paradoxicalresponseâ€? probably can be associated with other events. Insufficient CD4+ T-cell repopulation oflymphoid tissues may be due to a thymus failure or a defect in bone marrow function. Lifelong infection,the toxic effect of antiviral drugs on T- and B-cell precursors, the stage of disease, and the lownumber of CD4+ T-cells before HAART may also account for thymus exhaustion and insufficient T-cellrenewal. Finally, an imbalance in the production of cytokines such as TNF, IL-2 and IL-7 may also bea crucial event for the induction of immune system failure.In patients in which CD4+ T-cells are not increased by HAART, therapeutic strategies aimed at increasingthese cells and reducing the risk of infections are needed. IL-2 and/or other cytokines may be ofbenefit in this setting.Some antiviral drugs may be better than others in immunologic reconstitution. Protease inhibitorsmay have additional, independent positive effects on the immune system. On the other hand, theremay be little rationale for using immunosuppressive agents such as cyclosporine or hydroxyurea inthis subgroup of immunologic nonresponder patients, as these molecules may increase T-cell declineand/or favor susceptibility to infections.