Background. Persistent low CD4⁺ cell counts are observed in 5%–27% of patients treated for human immunodeficiency virus (HIV)—1 infection despite their having prolonged undetectable plasma viral loads.

Methods. To understand the possible mechanisms of this discordant immunological situation, a prospective transsectional case-control study was designed. HIV-1—infected subjects who had a plasma viral load <200 copies/ mL for >1 year were considered to be case patients if their CD4⁺ cell count was <250/mm³; control patients had CD4⁺ cell counts >500/mm³ and were matched by sex, age, and nadir CD4⁺ cell count to case patients. T cell proliferation after stimulation with various antigens, T cell subset counts, T cell rearrangement excision circles (TRECs), T cells undergoing apoptosis, cytokines influencing apoptosis, and cellular proviral DNA and plasma viral RNA persistence were assessed.

Results. Compared with the 19 control patients, the 19 case patients had undistinguishable lymphoproliferative responses to candidin and cytomegalovirus, fewer naive CD4⁺ cells (CD45RA⁺62L⁺, 23%±13% vs. 47%±14%; P<.0001), lower thymic output (1.28 vs. 3.95 TRECs/µL of blood; P=.0015), increased cell death by apoptosis (spontaneous, 23.2%±8.3% vs. 11.9%±8.4% [P=.02]; Fas induced, 38.6%±13.7% vs. 16.4%±8.0% [P=.004]), higher levels of plasma soluble tumor necrosis factor receptor II (9.6 vs. 5.3 ng/mL; P=.0058), and undistinguishable plasma HIV-1 and cellular proviral DNA loads.

Conclusions. The mechanisms responsible for the low-level regeneration of CD4⁺ cells involve, at least, deficiency in the regeneration of central CD4⁺ cells and excessive apoptosis.