Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection

Immune control of human immunodeficiency virus (HIV) is not restored by hig hly active antiretroviral therapies (HAART) during chronic infection. We ex amined the capacity of repeated structured therapeutic interruptions (STI) to restore HIV-specific CD4 and CD8 T-cell responses that controlled virus production. Eleven STI (median duration, 7 days; ranges, 4 to 24 days) were performed in three chronically HIV-infected patients with CD4 counts above 400/mm(3) and less than 200 HIV RNA copies/ml after 18 to 21 months of HAA RT; treatment resumed after 1 week or when virus became detectable. HIV-spe cific T-cell responses were analyzed by proliferation, gamma interferon (IF N-gamma.) production, and enzyme-linked immunospot assays. Seven virus rebo unds were observed (median, 4,712 HIV-1 RNA copies/ml),vith a median of 7 d ays during which CD4 and CD8 counts did not significantly change. After tre atment resumed, the viral load returned below 200 copies/ml within 3 weeks. Significant CD4 T-cell proliferation and IFN-gamma production against HIV p24 appeared simultaneously with or even before the virus rebounds in all p atients. These CD4 responses lasted for less than 3 weeks and disappeared b efore therapeutic control of the virus had occurred. Increases in the numbe rs of HIV-specific CD8 T cells were delayed compared to changes in HIV-spec ific CD4 T-cell responses. No delay or increase in virus doubling time was observed after repeated STI, Iterative reexposure to HIV during short STI i n chronically infected patients only transiently mobilized HIV-specific CD4 T1-helper cells, which might be rapidly altered by virus replication. Such kinetics might explain the failure at delaying subsequent virus rebounds a nd raises concerns about strategies based on STI to restore durable HIV-spe cific T-cell responses in chronic HIV infection.