NHC Key Laboratory of AIDS Immunology (China Medical University), National Clinical Research Center for Laboratory Medicine, The First Affiliated Hospital of China Medical University, 155 Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.
Key Laboratory of AIDS Immunology, Chinese Academy of Medical Sciences, Shenyang, 110001, China.
BMC Immunol. 2022 Apr 2;23(1):15. doi: 10.1186/s12865-022-00491-7.
Identifying immunogens which can elicit effective T cell responses against human immunodeficiency virus type 1 (HIV-1) is important for developing a T-cell based vaccine. It has been reported that human leukocyte antigen (HLA)-B13-restricted T-cell responses contributed to HIV control in subtype B' and C infected individuals. However, the kinetics of B13-restricted T-cell responses, viral evolution within epitopes, and the impact on disease progression in CRF01_AE subtype HIV-1-infected men who have sex with men (MSM) are not known.
Interferon-γ ELISPOT assays and deep sequencing of viral RNAs were done in 14 early HLA-B*13-positive CRF01_AE subtype HIV-1-infected MSM. We found that responses to RQEILDLWV (Nef, RV9), GQMREPRGSDI (Gag, GI11), GQDQWTYQI (Pol, GI9), and VQNAQGQMV (Gag, VV9) were dominant. A higher relative magnitude of Gag-specific T-cell responses, contributed to viral control, whereas Nef-specific T-cell responses were associated with rapid disease progression. GI11 (Gag) was conserved and strong GI11 (Gag)-specific T-cell responses showed cross-reactivity with a dominant variant, M228I, found in 3/12 patients; GI11 (Gag)-specific T-cell responses were positively associated with CD4 T-cell counts (R = 0.716, P = 0.046). Interestingly, the GI9 (Pol) epitope was also conserved, but GI9 (Pol)-specific T-cell responses did not influence disease progression (P > 0.05), while a D490G variant identified in one patient did not affect CD4 T-cell counts. All the other epitopes studied [VV9 (Gag), RQYDQILIEI (Pol, RI10), HQSLSPRTL (Gag, HL9), and RQANFLGRL (Gag RL9)] developed escape mutations within 1 year of infection, which may have contributed to overall disease progression. Intriguingly, we found early RV9 (Nef)-specific T-cell responses were associated with rapid disease progression, likely due to escape mutations.
Our study strongly suggested the inclusion of GI11 (Gag) and exclusion of RV9 (Nef) for T-cell-based vaccine design for B*13-positive CRF01_AE subtype HIV-1-infected MSM and high-risk individuals.
鉴定能够诱导针对人类免疫缺陷病毒 1 型（HIV-1）的有效 T 细胞反应的免疫原对于开发基于 T 细胞的疫苗非常重要。据报道，人类白细胞抗原（HLA）-B13 限制性 T 细胞反应有助于控制 B'和 C 亚型感染个体中的 HIV。然而，B13 限制性 T 细胞反应的动力学、表位内的病毒进化以及对 CRF01_AE 亚型 HIV-1 感染的男男性行为者（MSM）疾病进展的影响尚不清楚。
对 14 例早期 HLA-B*13 阳性 CRF01_AE 亚型 HIV-1 感染的 MSM 进行了干扰素-γ ELISPOT 检测和病毒 RNA 的深度测序。我们发现，对 RQEILDLWV（Nef，RV9）、GQMREPRGSDI（Gag，GI11）、GQDQWTYQI（Pol，GI9）和 VQNAQGQMV（Gag，VV9）的反应占主导地位。较高的 gag 特异性 T 细胞反应的相对幅度有助于病毒控制，而 nef 特异性 T 细胞反应与快速疾病进展相关。GI11（Gag）是保守的，强烈的 GI11（Gag）特异性 T 细胞反应显示与在 3/12 名患者中发现的主导变体 M228I 具有交叉反应性；GI11（Gag）特异性 T 细胞反应与 CD4 T 细胞计数呈正相关（R=0.716，P=0.046）。有趣的是，GI9（Pol）表位也是保守的，但 GI9（Pol）特异性 T 细胞反应并不影响疾病进展（P>0.05），而在一名患者中发现的 D490G 变体并未影响 CD4 T 细胞计数。我们研究的所有其他表位[VV9（Gag）、RQYDQILIEI（Pol，RI10）、HQSLSPRTL（Gag，HL9）和 RQANFLGRL（Gag RL9）]在感染后 1 年内都发生了逃逸突变，这可能导致了整体疾病进展。有趣的是，我们发现早期 RV9（Nef）特异性 T 细胞反应与快速疾病进展相关，可能是由于逃逸突变。
我们的研究强烈表明，对于 B*13 阳性 CRF01_AE 亚型 HIV-1 感染的 MSM 和高危人群，应将 GI11（Gag）纳入 T 细胞疫苗设计，而排除 RV9（Nef）。
