Gay Cynthia L, DeBenedette Mark A, Tcherepanova Irina Y, Gamble Alicia, Lewis Whitney E, Cope Anna B, Kuruc JoAnn D, McGee Kara S, Kearney Mary F, Coffin John M, Archin Nancie M, Hicks Charles B, Eron Joseph J, Nicolette Charles A, Margolis David M
1 University of North Carolina HIV Cure Center , Chapel Hill, North Carolina.
2 Department of Medicine, University of North Carolina Chapel Hill , Chapel Hill, North Carolina.
AIDS Res Hum Retroviruses. 2018 Jan;34(1):111-122. doi: 10.1089/aid.2017.0071. Epub 2017 Jun 21.
AGS-004 consists of matured autologous dendritic cells co-electroporated with in vitro transcribed RNA encoding autologous HIV antigens. In an open-label, single arm sub-study of AGS-004-003, AGS-004 was administered monthly to suppressed participants who started antiretroviral therapy (ART) during acute HIV infection. HIV-1 specific T cell responses were measured by multicolor flow cytometry after 3-4 doses. The frequency of resting CD4 T-cell infection (RCI) was measured by quantitative viral outgrowth assay. Participants demonstrating increased immune response postvaccination were eligible for analytic treatment interruption (ATI). AGS-004 induced a positive immune response defined as ≥2-fold increase from baseline in the number of multifunctional HIV-1 specific CD28/CD45RA CD8 effector/memory cytoxic T-lymphocytes (CTLs) in all six participants. All participants underwent ATI with rebound viremia at a median of 29 days. Immune correlates between time to viral rebound and the induction of effector CTLs were determined. Baseline RCI was low in most participants (0.043-0.767 IUPM). One participant had a >2-fold decrease (0.179-0.067 infectious units per million [IUPM]) in RCI at week 10. One participant with the lowest RCI had the longest ATI. AGS-004 dendritic cell administration increased multifunctional HIV-specific CD28/CD45RA CD8 memory T cell responses in all participants, but did not permit sustained ART interruption. However, greater expansion of CD28/CCR7/CD45RA CD8 effector T cell responses correlated with a longer time to viral rebound. AGS-004 may be a useful tool to augment immune responses in the setting of latency reversal and eradication strategies.
AGS-004由与体外转录的编码自体HIV抗原的RNA共电穿孔的成熟自体树突状细胞组成。在AGS-004-003的一项开放标签、单臂子研究中，每月给在急性HIV感染期间开始抗逆转录病毒疗法（ART）且病情得到抑制的参与者施用AGS-004。在3-4剂后通过多色流式细胞术测量HIV-1特异性T细胞反应。通过定量病毒生长测定法测量静息CD4 T细胞感染（RCI）的频率。证明接种疫苗后免疫反应增强的参与者有资格进行分析性治疗中断（ATI）。在所有六名参与者中，AGS-004诱导了一种阳性免疫反应，定义为多功能HIV-1特异性CD28/CD45RA CD8效应/记忆细胞毒性T淋巴细胞（CTL）数量较基线增加≥2倍。所有参与者均进行了ATI，中位29天时出现病毒血症反弹。确定了病毒反弹时间与效应CTL诱导之间的免疫相关性。大多数参与者的基线RCI较低（0.043-0.767感染单位/百万[IUPM]）。一名参与者在第10周时RCI下降>2倍（从0.179降至0.067感染单位/百万[IUPM]）。一名RCI最低的参与者ATI持续时间最长。施用AGS-004树突状细胞增加了所有参与者中多功能HIV特异性CD28/CD45RA CD8记忆T细胞反应，但不允许持续中断ART。然而，CD28/CCR7/CD45RA CD8效应T细胞反应的更大扩增与病毒反弹时间延长相关。在潜伏逆转和根除策略的背景下，AGS-004可能是增强免疫反应的有用工具。
