Autograft HIV-DNA load predicts HIV-1 peripheral reservoir after stem cell transplantation for AIDS-related lymphoma patients

Abstract

Autologous stem cell transplantation (ASCT) is a widely used procedure for AIDS-related lymphomas, and it represents an opportunity to evaluate strategies curing HIV-1 infection. The association of autograft HIV-DNA load with peripheral blood HIV-1 reservoir before ASCT and its contribution in predicting HIV-1 reservoir size and stability during combination antiretroviral therapy (cART) after transplantation are unknown. Aiming to obtain information suggesting new functional cure strategies by ASCT, we retrospectively evaluated HIV-DNA load in autograft and in peripheral blood before and after transplantation in 13 cART-treated HIV-1 relapse/refractoring lymphoma patients. Among them seven discontinued cART after autograft infusion. HIV-DNA was evaluated by a sensitive quantitative real-time polymerase chain reaction (PCR). After debulking chemotherapy/mobilization, the autograft HIV-1 reservoir was higher than and not associated with the peripheral HIV-1 reservoir at baseline [median 215 HIV-DNA copies/10(6) autograft mononuclear cells, range 13-706 vs. 82 HIV-DNA copies/10(6) peripheral blood mononuclear cells (PBMCs), range 13-479, p = 0.03]. After high dose chemotherapy and autograft infusion, HIV-DNA levels reached a plateau between month 6 and 12 of follow-up. No association was found between peripheral HIV-DNA levels at baseline and after infusion in both cART interrupting and not interrupting patients. Only in the last subgroup, a stable significant linear association between autograft and peripheral blood HIV-1 reservoir emerged from month 1 (R(2) = 0.84, p = 0.01) to month 12 follow-up (R(2) = 0.99, p = 0.0005). In summary, autograft HIV-1 reservoir size could be influenced by the mobilization phase and predicts posttransplant peripheral HIV-1 reservoir size in patients on continuous cART. These findings could promote new research on strategies reducing the HIV-1 reservoir by using the ASCT procedure.

FIG. 1.

Outline of autologous stem cell transplantation (ASCT) procedure and timing of parameter evaluation. DCT, debulking chemotherapy; G-CSF, granulocyte colony-stimulating factor; HDC, high dose chemotherapy.

FIG. 2.

HIV-1 reservoir posttransplant dynamics in continuously (top) and interrupted combined antiretroviral therapy (cART)-treated patients (bottom).

FIG. 3.

(a) Linear regression between reservoir size in the autograft vs. reservoir size in peripheral blood at baseline (before HDC) in overall patients: R²=0.04, slope=0.41, p (slope≠0)=0.53; (b) linear regression between reservoir size in peripheral blood at month 6 or 12 vs. reservoir size in peripheral blood at baseline (before HDC) in overall patients: R²=0.0001, slope=–0.04, p (slope≠0)=0.97; (c) linear regression and 95% CI (curved lines) between reservoir size in peripheral blood at month 1 or 3 vs. reservoir size in autograft, continuously cART-treated patients: R²=0.89, slope=0.55, p (slope≠0)=0.0044; interrupted cART patients: R²=0.008, slope=0.03, p (slope≠0)=0.85; (d) linear regression and 95% CI between reservoir size in peripheral blood at month 6 or 12 vs. reservoir size in autograft, continuously cART-treated patients: R²=0.99, slope=0.56, p (slope≠0)<0.0001; interrupted cART patients: R²=0.09, slope=0.61, p (slope≠0)=0.51. (e) linear regression between reservoir size per million CD4 in peripheral blood at month 1 or 3 vs. reservoir size per million CD4 in autograft, continuously cART-treated patients: R²=0.30, slope=0.46, p (slope≠0)=0.26; interrupted cART patients: R²=0.004, slope=0.02, p (slope≠0)=0.91; (f) linear regression and 95% CI between reservoir size per million CD4 in peripheral blood at month 6 or 12 vs. reservoir size per million CD4 in autograft, continuously cART-treated patients: R²=0.78, slope=0.92, p (slope≠0)=0.019; interrupted cART patients: R²=0.004, slope=–0.15, p (slope≠0)=0.89. HDC, high dose chemotherapy; cART, combination antiretroviral therapy; CI, confidence intervals; AMCs, autograft mononuclear cells; PBMCs, peripheral blood mononuclear cells. black triangles, continuously cART-treated patients; black diamonds, interrupted cART patients before interruption; open diamonds, interrupted cART patients after interruption; gray triangle, continuously cART-treated patients at month 1 (c–e) or month 6 (d–f).