Chakraborty Rana, Morel Anne-Sophie, Sutton Julian K, Appay Victor, Ripley Ruth M, Dong Tao, Rostron Tim, Ogola Simon, Palakudy Tresa, Musoke Rachel, D'Agostino Angelo, Ritter Mary, Rowland-Jones Sarah L
Pediatric Infectious Diseases Unit, St. George's Hospital, London, United Kingdom.
J Immunol. 2005 Jun 15;174(12):8191-9. doi: 10.4049/jimmunol.174.12.8191.
Without treatment most HIV-1-infected children in Africa die before their third birthday (>89%) and long-term nonprogressors are rare. The mechanisms underlying nonprogression in HIV-1-infected children are not well understood. In the present study, we examined potential correlates of delayed HIV disease progression in 51 HIV-1-infected African children. Children were assigned to progression subgroups based on clinical characterization. HIV-1-specific immune responses were studied using a combination of ELISPOT assays, tetramer staining, and FACS analysis to characterize the magnitude, specificity, and functional phenotype of HIV-1-specific CD8(+) and CD4(+) T cells. Host genetic factors were examined by genotyping with sequence-specific primers. HIV-1 nef gene sequences from infecting isolates from the children were examined for potential attenuating deletions. Thymic output was measured by T cell rearrangement excision circle assays. HIV-1-specific CD8(+) T cell responses were detected in all progression groups. The most striking attribute of long-term survivor nonprogressors was the detection of HIV-1-specific CD4(+) Th responses in this group at a magnitude substantially greater than previously observed in adult long-term nonprogressors. Although long-term survivor nonprogressors had a significantly higher percentage of CD45RA(+)CD4(+) T cells, nonprogression was not associated with higher thymic output. No protective genotypes for known coreceptor polymorphisms or large sequence deletions in the nef gene associated with delayed disease progression were identified. In the absence of host genotypes and attenuating mutations in HIV-1 nef, long-term surviving children generated strong CD4(+) T cell responses to HIV-1. As HIV-1-specific helper cells support anti-HIV-1 effector responses in active disease, their presence may be important in delaying disease progression.
未经治疗的非洲大多数感染HIV-1的儿童在三岁生日前死亡（超过89%），长期不进展者很少见。HIV-1感染儿童疾病不进展的潜在机制尚不清楚。在本研究中，我们检测了51名感染HIV-1的非洲儿童中艾滋病进展延迟的潜在相关因素。根据临床表现将儿童分为疾病进展亚组。使用ELISPOT检测、四聚体染色和FACS分析相结合的方法研究HIV-1特异性免疫反应，以表征HIV-1特异性CD8(+)和CD4(+) T细胞的数量、特异性和功能表型。通过序列特异性引物基因分型检测宿主遗传因素。检测儿童感染分离株的HIV-1 nef基因序列，寻找潜在的减毒缺失。通过T细胞重排切除环检测来测量胸腺输出。在所有疾病进展组中均检测到HIV-1特异性CD8(+) T细胞反应。长期存活不进展者最显著的特征是该组中检测到的HIV-1特异性CD4(+) Th反应，其强度大大高于之前在成人长期不进展者中观察到的水平。虽然长期存活不进展者的CD45RA(+)CD4(+) T细胞百分比显著更高，但疾病不进展与更高的胸腺输出无关。未发现已知共受体多态性或与疾病进展延迟相关的nef基因大序列缺失的保护性基因型。在没有宿主基因型和HIV-1 nef减毒突变的情况下，长期存活儿童对HIV-1产生了强烈的CD4(+) T细胞反应。由于HIV-1特异性辅助细胞在活动性疾病中支持抗HIV-1效应反应，它们的存在可能对延缓疾病进展很重要。
