Gondois-Rey Françoise, Biancotto Angelique, Fernandez Marcelo Antonio, Bettendroffer Lise, Blazkova Jana, Trejbalova Katerina, Pion Marjorie, Hirsch Ivan
INSERM U372, boulevard Lei Roure, 13009 Marseille, France.
J Virol. 2006 Jan;80(2):854-65. doi: 10.1128/JVI.80.2.854-865.2006.
The persistence of human immunodeficiency virus type 1 (HIV-1) in memory CD4+ T cells is a major obstacle to the eradication of the virus with current antiretroviral therapy. Here, we investigated the effect of the activation status of CD4+ T cells on the predominance of R5 and X4 HIV-1 variants in different subsets of CD4+ T cells in ex vivo-infected human lymphoid tissues and peripheral blood mononuclear cells (PBMCs). In these cell systems, we examined the sensitivity of HIV replication to reverse transcriptase inhibitors. We demonstrate that R5 HIV-1 variants preferentially produced productive infection in HLA-DR- CD62L- CD4+ T cells. These cells were mostly in the G1b phase of the cell cycle, divided slowly, and expressed high levels of CCR5. In contrast, X4 HIV-1 variants preferentially produced productive infection in activated HLA-DR+ CD62L+ CD4+ T cells, which expressed high levels of CXCR4. The abilities of the nucleoside reverse transcriptase inhibitors (NRTI) zidovudine and lamivudine to stop HIV-1 replication were 20 times greater in activated T cells than in slowly dividing HLA-DR- CD62L- CD4+ T cells. This result, demonstrated both in a highly physiologically relevant ex vivo lymphoid tissue model and in PBMCs, correlated with higher levels of thymidine kinase mRNA in activated than in slowly dividing HLA-DR- CD62L- CD4+ T cells. The non-NRTI nevirapine was equally efficient in both cell subsets. The lymphoid tissue and PBMC-derived cell systems represent well-defined models which could be used as new tools for the study of the mechanism of resistance to HIV-1 inhibitors in HLA-DR- CD62L- CD4+ T cells.
1型人类免疫缺陷病毒（HIV-1）在记忆性CD4+ T细胞中的持续存在是目前抗逆转录病毒疗法根除该病毒的主要障碍。在此，我们研究了CD4+ T细胞的激活状态对体外感染的人淋巴组织和外周血单个核细胞（PBMC）中不同CD4+ T细胞亚群里R5和X4 HIV-1变体优势的影响。在这些细胞系统中，我们检测了HIV复制对逆转录酶抑制剂的敏感性。我们证明，R5 HIV-1变体优先在HLA-DR- CD62L- CD4+ T细胞中产生有效感染。这些细胞大多处于细胞周期的G1b期，分裂缓慢，并高水平表达CCR5。相反，X4 HIV-1变体优先在活化的HLA-DR+ CD62L+ CD4+ T细胞中产生有效感染，这些细胞高水平表达CXCR4。核苷类逆转录酶抑制剂（NRTI）齐多夫定和拉米夫定在活化T细胞中阻止HIV-1复制的能力比在缓慢分裂的HLA-DR- CD62L- CD4+ T细胞中高20倍。这一结果在高度生理相关的体外淋巴组织模型和PBMC中均得到证实，与活化的HLA-DR- CD62L- CD4+ T细胞中胸苷激酶mRNA水平高于缓慢分裂的细胞相关。非核苷类逆转录酶抑制剂奈韦拉平在两个细胞亚群中的效率相同。淋巴组织和PBMC来源的细胞系统代表了明确的模型，可作为研究HLA-DR- CD62L- CD4+ T细胞中HIV-1抑制剂耐药机制的新工具。
