Background: A discordant response to highly active antiretroviral therapy (HAART) occurs when CD4 T-cell counts are stable or increased over time despite detectable viral load (VL).  The role of humoral and cellular immune responses in this phenomenon are still undetermined.

Methods: 30 HIV+ patients (22 male, 8 female; 17 white, 13 African American) on protease inhibitor (PI)-based HAART were studied in 3 groups: Failure (F): VL increasing, CD4 decreasing; Discordant (D): VL 500-5000 copies/mL, CD4 > 200/mm³ with increasing trend sustained > 2 years; Success (S): VL < 50 copies/mL, CD4 > 200/mm³ with increasing trend sustained > 2 years.  All subjects were treatment adherent as judged by history and resistance profile.  Measures of immune function included: CD8 response to gag, rev, tat, vpr antigens by interferon-γ ELISpot; quantitation of T-cell subsets and CD38 antibodies bound per cell (ABC) by flow cytometry; CD4 and CD8 sjTRECs; serum IgG responses to gp120, gp41 peptide, MN V3 peptide.  Comparisons between groups were made by Wilcoxon Rank Sum, Kruskal-Wallis, or Fisher’s Exact Test. 

Results: Groups did not differ significantly in age, gender, IgG responses, or CD4/CD8 sjTRECs, although sjTRECs trended lower in D vs S or F.  Cellular activation as measured by CD38+HLA-DR+ expression trended greater for F vs D on CD4 and CD8 cells (median CD4: F=15% D=11% p=0.06; CD8: F=37% D=31% p=0.08).  Median CD38 ABC was significantly greater for all T-cell subsets for F vs D (naïve CD4: F=15323, D=8911, p=0.01; memory CD4: F=12319, D=6333, p=0.005; activated CD4: F=17297, D=11119, p=0.04; activated CD8: F=20357, D=8413, p=0.008).  CD8 responses to gag, tat were greater in D vs S or F.  (Median spot forming cells/10⁶ cells: gag D=1113, S=434, F=760; D vs S:p=0.02, D vs F:p=0.2; tat D=65, S=16, F=41; D vs S:p=0.06, D vs F:p=0.6)  The ELISpot assay showed a detectable CD4 response to gag in 5/9 D subjects, 3/8 F, 0/10 S.

Conclusions: Patients with a discordant CD4/VL response to PI-based HAART have decreased immune activation and enhanced HIV-directed CD4 T-helper and CD8 responses that may contribute to control of HIV replication and immune homeostasis.