在一个人类传播模型中，复制能力降低的耐药性HIV-1变体的传播减少。

Diminished transmission of drug resistant HIV-1 variants with reduced replication capacity in a human transmission model.

作者信息

Pingen Marieke, Sarrami-Forooshani Ramin, Wensing Annemarie M J, van Ham Petra, Drewniak Agata, Boucher Charles A B, Geijtenbeek Teunis B H, Nijhuis Monique

机构信息

Virology, Department of Medical Microbiology, University Medical Center Utrecht, Heidelberglaan 100, 3584CX, Utrecht, the Netherlands.

Department of Virology, Erasmus Medical Center, Rotterdam, the Netherlands.

出版信息

Retrovirology. 2014 Dec 14;11:113. doi: 10.1186/s12977-014-0113-9.

DOI:10.1186/s12977-014-0113-9

PMID:25499671

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4272521/

Abstract

BACKGROUND

Different patterns of drug resistance are observed in treated and therapy naïve HIV-1 infected populations. Especially the NRTI-related M184I/V variants, which are among the most frequently encountered mutations in treated patients, are underrepresented in the antiretroviral naïve population. M184I/V mutations are known to have a profound effect on viral replication and tend to revert over time in the new host. However it is debated whether a diminished transmission efficacy of HIV variants with a reduced replication capacity can also contribute to the observed discrepancy in genotypic patterns. As dendritic cells (DCs) play a pivotal role in HIV-1 transmission, we used a model containing primary human Langerhans cells (LCs) and DCs to compare the transmission efficacy M184 variants (HIV-M184V/I/T) to HIV wild type (HIV-WT). As control, we used HIV harboring the NNRTI mutation K103N (HIV-K103N) which has a minor effect on replication and is found at a similar prevalence in treated and untreated individuals.

RESULTS

In comparison to HIV-WT, the HIV-M184 variants were less efficiently transmitted to CCR5(+) Jurkat T cells by both LCs and DCs. The transmission rate of HIV-K103N was slightly reduced to HIV-WT in LCs and even higher than HIV-WT in DCs. Replication experiments in CCR5(+) Jurkat T cells revealed no apparent differences in replication capacity between the mutant viruses and HIV-WT. However, viral replication in LCs and DCs was in concordance with the transmission results; replication by the HIV-M184 variants was lower than replication by HIV-WT, and the level of replication of HIV-K103N was intermediate for LCs and higher than HIV-WT for DCs.

CONCLUSIONS

Our data demonstrate that drug resistant M184-variants display a reduced replication capacity in LCs and DCs which directly impairs their transmission efficacy. As such, diminished transmission efficacy may contribute to the lower prevalence of drug resistant variants in therapy naive individuals.

摘要

背景

在接受治疗和未接受过治疗的HIV-1感染人群中观察到不同的耐药模式。特别是与核苷类逆转录酶抑制剂（NRTI）相关的M184I/V变异体，虽然是接受治疗患者中最常出现的突变之一，但在未接受抗逆转录病毒治疗的人群中所占比例较低。已知M184I/V突变对病毒复制有深远影响，并且在新宿主中往往会随时间逆转。然而，复制能力降低的HIV变异体传播效率降低是否也能导致观察到的基因型模式差异，这一点存在争议。由于树突状细胞（DC）在HIV-1传播中起关键作用，我们使用了一个包含原代人朗格汉斯细胞（LC）和DC的模型，比较M184变异体（HIV-M184V/I/T）与HIV野生型（HIV-WT）的传播效率。作为对照，我们使用携带非核苷类逆转录酶抑制剂（NNRTI）突变K103N的HIV（HIV-K103N），该突变对复制影响较小，在接受治疗和未接受治疗的个体中出现频率相似。

结果

与HIV-WT相比，HIV-M184变异体被LC和DC传递至CCR5(+) Jurkat T细胞的效率较低。HIV-K103N在LC中的传递率略低于HIV-WT，而在DC中甚至高于HIV-WT。在CCR5(+) Jurkat T细胞中的复制实验显示，突变病毒与HIV-WT之间的复制能力无明显差异。然而，在LC和DC中的病毒复制与传递结果一致；HIV-M184变异体的复制低于HIV-WT，HIV-K103N在LC中的复制水平处于中间，在DC中高于HIV-WT。