Spectrum of CD4 T-cell recovery during prolonged treatment with highly active antiretroviral therapy

The study of a large cohort of patients has confirmed that one third of HIV-infected patients on highly active antiretroviral therapy failed to raise their CD4 T-cell counts to pre-infection levels. Although we do not know all the factors that interfere with the reconstitution of CD4 T cells, new advances in this field may shed some light on this phenomenon.

The description of new CD4-naive and memory subpopulations has shown that HIV infection can lead to the depletion in vivo of all different CD4 T-cell subpopulations, and that this process can be partly reversed by highly active antiretroviral therapy. Nevertheless, the effect of highly active antiretroviral therapy on the functional reconstitution of these subpopulations is still a matter of debate, particularly in the light of some interesting and relevant recent developments. First, regulatory T cells may play an important role in the control of HIV by inhibiting specific immune responses and inducing tolerance to HIV antigens. In addition, tolerance might also be induced by the presence of HIV in the thymus as the thymus is functional in a substantial proportion of HIV-infected patients. Second, immune compartments other than peripheral blood might interfere with immune reconstitution, for example, intestinal CD4 T cells are particularly sensitive to HIV depletion. Finally, co-infections with cytomegalovirus or other pathogens might also affect the outcome of the disease.

The clinical relevance of all these observations is currently unknown and highlights the complexity of the mechanisms involved in the pathogenesis of HIV infection.