Lymphoid Tissue Damage in HIV-1 Infection Depletes Naïve T Cells and Limits T Cell Reconstitution after Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) can suppress HIV-1 replication and normalize the chronic immune activation associated with infection, but restoration of naïve CD4+ T cell populations is slow and usually incomplete for reasons that have yet to be determined. We tested the hypothesis that damage to the lymphoid tissue (LT) fibroblastic reticular cell (FRC) network contributes to naïve T cell loss in HIV-1 infection by restricting access to critical factors required for T cell survival. We show that collagen deposition and progressive loss of the FRC network in LTs prior to treatment restrict both access to and a major source of the survival factor interleukin-7 (IL-7). As a consequence, apoptosis within naïve T cell populations increases significantly, resulting in progressive depletion of both naïve CD4+ and CD8+ T cell populations. We further show that the extent of loss of the FRC network and collagen deposition predict the extent of restoration of the naïve T cell population after 6 month of HAART, and that restoration of FRC networks correlates with the stage of disease at which the therapy is initiated. Because restoration of the FRC network and reconstitution of naïve T cell populations are only optimal when therapy is initiated in the early/acute stage of infection, our findings strongly suggest that HAART should be initiated as soon as possible. Moreover, our findings also point to the potential use of adjunctive anti-fibrotic therapies to avert or moderate the pathological consequences of LT fibrosis, thereby improving immune reconstitution.

高效抗反转录病毒疗法（Highly Active Antiretroviral Therapy, HAART）可抑制HIV-1复制并使感染相关的慢性免疫活化恢复正常，但幼稚CD4+ T细胞群的重建速度缓慢且往往不完全，其具体机制尚未明确。本研究验证了下述假说：HIV-1感染中，淋巴组织（lymphoid tissue, LT）成纤维网状细胞（fibroblastic reticular cell, FRC）网络受损，会通过限制T细胞存活所需关键因子的可及性，导致幼稚T细胞丢失。研究结果显示，治疗前淋巴组织内的胶原沉积与成纤维网状细胞网络的进行性丢失，会同时限制存活因子白细胞介素-7（interleukin-7, IL-7）的可及性及其主要来源。由此，幼稚T细胞群的细胞凋亡显著增加，最终导致幼稚CD4+及CD8+ T细胞群进行性耗竭。本研究进一步证实，成纤维网状细胞网络的丢失程度与胶原沉积程度，可预测高效抗反转录病毒疗法治疗6个月后幼稚T细胞群的重建效果；且成纤维网状细胞网络的重建情况与治疗启动时的疾病分期相关。由于仅当感染处于早期/急性期时启动治疗，成纤维网状细胞网络的重建与幼稚T细胞群的恢复才能达到最佳状态，因此本研究结果强烈提示，高效抗反转录病毒疗法应尽早启动。此外，本研究结果还提示，辅助性抗纤维化疗法或可用于预防或缓解淋巴组织纤维化的病理后果，从而改善免疫重建效果。