361a
Stronger Memory and Lower Effector T Cell Responses to HIV in Patients with Long-term Undetectable HIV Viral Loads under Sustained ART Compared to HIV Controllers
Amelie Guihot*1,2, G Breton3, R Tubiana2, B Amellal4, A G Marcelin4, D Costagliola5, A Samri1, C Katlama2, B Autran1, G Carcelain1, and ALT-ANRS CO 15 study group and DECAMUNE study group
1Hosp Pitie-Salpetriere, Paris, France; 2Hosp Pitie-Salpetriere, Paris, France; 3Hosp Pitie-Salpetriere, Paris, France; 4Hosp Pitie-Salpetriere, Paris, France; and 5INSERM UMR S720, Paris, France
Background: We aimed to explore the quality and
intensity of immunity in patients with sustained (10 years) HIV virological
control. Long-term undetectable patients (LTUp) were compared with short-term
undetectable patients (STUp) and long-term non-progressors (LTNP) controlling
HIV (HIVc).
Methods: We prospectively studied 16 LTUp and 11
STUp who had been treated with HAART for 10 and 3 years, respectively. Patients
were naïve at ART initiation, had no interruption, and had HIV viral loads <200
copies/mL; 11 HIVc had viral loads of <200 copies/mL and CD4 counts >600/mm3
for more than 6 years, without ART. CD4 and CD8 differentiation (CD45RA, CD62L,
CD38, CD25, HLA-DR), proliferative and enzyme-linked immunosorbent spot (ELISpot)
interferon (IFN) -g responses to p24
and cytomegalovirus (CMV) proteins or peptides, intracellular cytokine staining
(ICS) (tumor necrosis factor [TNF] -a,
CD107a, MIP1-b, interleukin-2 [IL-2])
CD8 responses to HIV peptides were studied. HIV cell-associated DNA was
quantified.
Results: Median CD4 counts were 662 (185 to -1111),
560 (182 to 1338), and 715 (669 to 902)/mm3 for LTUp, STUp, and
HIVc, respectively; nadirs were comparable; slopes of CD4 increase for LTUp were
42 and 5.1 CD4/year between year 1–5 and 6–10, respectively. Naïve CD4+45RA+62L+
cells and T cell activation markers normalized in LTUp, except for HLA-DR on
CD8+ cells. Proliferative responses to p24 were detected in 9 of 14 LTUp,
3 of 11 STUp, and 6 of 11 HIVc, with median 13 (2 to 80), 3 (1 to 25), and 3 (1
to 74) stimulation index, respectively (LTUp-STUp: p = 0.02, LTUp-HIVc:
NS, Mann-Whitney test). BrdU incorporation confirmed high CD4+ HIV-p24-specific
responses in 7 LTUp (median 6% [1 to 13%] of CD4+ cells]. Proliferative
responses to cytomegalovirus (CMV) were also higher in LTUp than STUp (p
= 0.03). In contrast, enzyme-linked immunosorbent spot (ELISpot) assay p24-specific
CD4 responses showed 3 of 11 LTUp, 5 of 9 STUp, and 5 of 7 HIVc responders, with
low frequencies: median 37 (0 to 200), 53 (0 to 1320), and 183 (0 to 430) spot-forming
colonies (SFC)/106 PBMC, respectively (LTUp-HIVc: p = 0.03).
HIV-specific CD8 cell responses were also lower in LTUp than in HIVc (11 of 14
and 8 of 8 responders, respectively; median frequencies 230 [0 to 4067] and 2202
[160 to 12,547] SFC/106 PBMC, respectively; p = 0.01), but were
poly-functional. Despite higher levels of HIV DNA in LTUp than HIVc (157 [52 to
632] and 30 [2 to 64] copies per cell, respectively; p <0.01]), no
correlation was found with HIV-specific T cell responses.
Conclusions: Patients with sustained virological
control during a 10-year period have higher anti-p24 proliferative memory CD4
cell responses, but lower CD4 and CD8 effector-memory cell responses against
HIV when compared to HIV controllers. These results offer new insights in
immune restoration during ART.
|
