Background: Most previous studies have shown that HIV-specific cytotoxic CD8⁺ lymphocytes (CTLs) tend to decline after suppressing viral replication with HAART. However, in some individuals CTL activity can be maintained or even develops after beginning HAART. Herein, we used tetrameric complexes to analyze the effect of HAART on the phenotype and function of Gag and Pol HIV specific CTLs in chronically HIV-infected patients (pts).

Methods: 26 HLA-A0201⁺ HIV-infected pts were analyzed. At least 2 samples were examined for each pt, 1 before initiating HAART and another after 6 months (mos) on treatment. Levels of tetramer-Gag and tetramer-Pol CTLs and their naive (CD45RA⁺CD27⁺), memory (CD45RA^-), and effector (CD45RA⁺CD27^-) subsets were measured by 4-color flow cytometry. Stimulation of PBMCs with Gag, Pol and control peptides was done to measure the ability of Tet⁺ cells to produce IFN-g.

Results: Fifty percent (50%) of patients had Tet⁺ cells before HAART. After beginning therapy, Tet⁺ cells declined steadily in most pts in parallel with viral load (VL) reductions. Most Tet⁺ cells had a memory phenotype, and their ability to produce IFN-g was reduced. These findings remained unchanged whereas on HAART. Moroever, 4 out of 13 subjects who did not have Tet⁺ cells at baseline showed de novo appearance of these cells in parallel with suppression of HIV replication with HAART. These 4 individuals had high VL at baseline and low but still detectable HIV-RNA while on HAART. In 1 of those pts which was followed for 2 yrs, with periods on and off treatment, the levels of TetGag⁺ cells fluctuated mirroring the fluctuations in VL, with Tet⁺ cells declining when viremia rebounded to high levels, and going up again with partial control of HIV replication with therapy.

Conclusions: High levels of HIV replication can impair HIV-specific immune responses. Tet⁺ cells may appear de novo after lowering viral replication with HAART as long as complete suppression is not attained. These results support that sustained low levels of virus replication may improve or even restore immune responses against HIV.