Paryad-Zanjani Sasan, Jagarapu Aditya, Piovoso Michael J, Zurakowski Ryan
bioRxiv. 2023 Feb 27:2023.02.18.529086. doi: 10.1101/2023.02.18.529086.
Lymph nodes (LNs) serve as a sanctuary site for HIV viruses due to the heterogeneous distribution of the antiretrovirals (ARVs) inside the LNs. There is an ongoing debate whether this represents ongoing cycles of viral replication in the LNs or merely residual virus production by latently infected cells. Previous work has claimed that the measured levels of genetic variation in proviruses sampled from the blood were inconsistent with ongoing replication. However, it is not clear what rate of variation is consistent with ongoing replication in small sanctuary sites. In this study, we used a spherically symmetric compartmental ODE model to track the HIV viral dynamics in the LN and predict the contribution of ongoing replication within the LN to the wholebody proviral pool in an ARV-suppressed patient. This model tracks the reaction-diffusion dynamics of uninfected, actively infected, and latently infected T-cells as well as free virus within the LN parenchyma and the blood, and distinguishes between latently infected cells created before ARV therapy and during ARV therapy. We simulated suppressive therapy beginning in year 5 post-infection. Each LN sanctuary site had a volume of 1 ml, and we considered cases of 1ml, 30ml, and 250ml total volume, which represent a single active sanctuary site, moderate systemic involvement, and involvement of the total lymphoid tissue. Viral load in the blood rapidly dropped and remained below the limit of detection in all cases but remained high in the LN sanctuary sites. Novel latent cells increased systemically over time but very slowly, taking between 25 and 50 years to reach 5% of the total latent pool, depending on the volume of lymphoid tissue involvement. Putative sanctuary sites in LNs are limited in volume and produce novel latent cells slowly. Assays to detect genetic drift due to such sites would require very deep sequencing if sampling only from the blood. Previous studies showing a lack of genetic drift are consistent with the expected contribution of ongoing replication in lymph node sanctuary sites.
由于抗逆转录病毒药物（ARVs）在淋巴结（LNs）内分布不均，淋巴结成为HIV病毒的庇护场所。关于这是代表着淋巴结内持续的病毒复制周期，还是仅仅是潜伏感染细胞产生的残留病毒，目前仍在争论中。先前的研究称，从血液中采样的前病毒中测得的基因变异水平与持续复制不一致。然而，尚不清楚何种变异率与小庇护场所中的持续复制相一致。在本研究中，我们使用了一个球对称的房室常微分方程模型来追踪淋巴结中的HIV病毒动力学，并预测在接受ARV治疗的患者中，淋巴结内持续复制对全身前病毒库的贡献。该模型追踪未感染、活跃感染和潜伏感染的T细胞以及淋巴结实质和血液中的游离病毒的反应扩散动力学，并区分ARV治疗前和治疗期间产生的潜伏感染细胞。我们模拟了感染后第5年开始的抑制治疗。每个淋巴结庇护场所的体积为1毫升，我们考虑了总体积为1毫升、30毫升和250毫升的情况，分别代表单个活跃庇护场所、中度全身受累和全淋巴组织受累。血液中的病毒载量迅速下降，在所有情况下都保持在检测限以下，但在淋巴结庇护场所中仍保持较高水平。新的潜伏细胞随着时间的推移在全身缓慢增加，但非常缓慢，根据淋巴组织受累的体积，需要25到50年才能达到总潜伏库的5%。淋巴结中的假定庇护场所体积有限，新潜伏细胞产生缓慢。如果仅从血液中采样，检测此类场所导致的基因漂移的检测方法将需要非常深度的测序。先前显示缺乏基因漂移的研究与淋巴结庇护场所中持续复制的预期贡献一致。
