Antiretroviral therapy (ART) started during acute or early HIV infection (AEHI) has multiple benefits, but its immunologic effects are not well defined. We hypothesized that early ART would limit antigen exposure and reduce T cell immune responses in a multinational, prospective, open-label study of early ART.
ACTG A5354 enrolled and rapidly initiated ART in adults with Fiebig stages I-V of AEHI at 30 sites in the Americas, Africa and Southeast Asia. Fiebig stage at start of ART was assigned retrospectively by centralized testing. A secondary endpoint of A5354 was to assess if timing of ART during AEHI influenced HIV-specific T cells after 48 weeks of ART. Comparisons were between pre-specified study Groups; Group 1 (G1) Fiebig I/II (n=49); Group 2 (G2) Fiebig III/IV (n=79); and Group 3 (G3) Fiebig V (n=60). Peripheral blood mononuclear cells were stimulated (6 h) with PTE peptide pools (NIH HIV Reagent Program) consisting of env, gag, nef, or pol peptides, SEB (positive control) or incubated without stimulation (negative control). Brefeldin A and CD107a antibody (for staining) were added during the 6 h incubation. Cells were stained for expression of CD3, CD4 and CD8 and intracellular CD40L, Mip1b, IFN-g and TNF-a and analyzed by flow cytometry excluding debris, doublets and dead. HIV DNA copies/million CD4 T cells was determined by qPCR.
Frequencies of T cells that expressed any one of the possible activation markers were diminished in G1 participants compared to other groups (Figure). Significant differences (Wilcoxon Test; p<0.05) were observed for gag- and pol-specific CD8+ and CD4 + T cell responses (G1 vs G2) as well as for nef-specific CD8+ T cells responses (G1 vs G3 and G2 vs G3). T cell polyfunction among cells expressing activation markers was similar across groups; modest, but significant (p<0.05) differences, were noted comparing G1 vs G2 for percentages of HIV-reactive CD4+ T cells expressing two functions after stimulation with env (median: 11.2 vs 9.0), nef (10.1 vs 8.8) or pol (10.7 vs 8.7). Frequencies of HIV-specific T cells were not correlated with total HIV DNA (|Spearman r| ? 0.15, p>0.07; unadjusted and adjusted for study groups) at week 48.
ART initiation in the earliest Fiebig stages (I/II) reduces frequencies but not polyfunction of HIV-specific T cells. Frequencies of HIV-infected cells that persist on ART do not appear to drive HIV-reactive T cells in adults treated during AEHI.