Wilson S E, Pedersen S L, Kunich J C, Wilkins V L, Mann D L, Mazzara G P, Tartaglia J, Celum C L, Sheppard H W
Division of Communicable Disease Control, California Department of Health Services, Berkeley 94704, USA.
AIDS Res Hum Retroviruses. 1998 Jul 20;14(11):925-37. doi: 10.1089/aid.1998.14.925.
A major objective of current HIV-1 vaccination strategies is the induction of HIV-1-specific CD8+ MHC class I-restricted CTL responses, which are suggested to play a pivotal role in viral clearance and protection against HIV-1 disease progression. However, the marked genetic diversity of HIV-1 and existence of distinct viral subtypes or clades could potentially hinder the development of a universally efficacious HIV-1 vaccine. In this study we examined HIV-1 intraclade (B(LAI) versus B(MN)) Env gp160-specific CTL reactivity in recently HIV-1 clade B-infected individuals. We further evaluated the extent of interclade CTL cross-recognition of the divergent A and C Env gp160 subtypes, that are highly prevalent in the global pandemic. Freshly isolated PBMCs were stimulated in vitro with autologous PBMCs infected with recombinant vaccinia vectors expressing HIV-1 env, gag, pol, and nef genes derived from HIV-1 clade B. All 13 of the 19 HIV-1-seropositive subjects who elicited significant clade B Env gp160LAI CD8+ CTL responses also demonstrated comparable levels of CTL cross-reactivity against clade C92BR025 Env gp160. Nine of these individuals also showed extensive interclade CTL cross-recognition of clade A92UG037 Env gp160. Two HLA class I B7 donors had nondetectable intraclade CTL response against B Env gp160MN, while generating significant intraclade B(LAI) and interclade (A and C) Env gp160 CTL cross-reactivity. These observations serve to underscore the central importance of the HLA background of individuals in determining the pattern of immune reactivity to natural HIV-1 infection and presumably vaccines. Five donors studied also demonstrated broad CTL cross-reactivity against clade A92UG037 Gag p55, Pol, and/or Nef antigens. In conclusion, this present study indicates that there is a considerable degree of CD8+ CTL cross-recognition of the highly divergent HIV-1 Env gp160 subtypes during early phases of HIV-1 infection. Such findings suggest that HIV-1 vaccines based on a single clade that can induce extensive cross-clade immunity may demonstrate utility in diverse geographical regions.
当前HIV-1疫苗接种策略的一个主要目标是诱导HIV-1特异性的CD8+MHC I类限制性CTL反应，据认为该反应在病毒清除以及预防HIV-1疾病进展中起关键作用。然而，HIV-1显著的基因多样性以及不同病毒亚型或分支的存在可能会阻碍通用有效HIV-1疫苗的研发。在本研究中，我们检测了近期感染HIV-1 B分支的个体中HIV-1分支内（B(LAI) 与B(MN)）Env gp160特异性CTL反应性。我们进一步评估了全球大流行中高度流行的不同A和C Env gp160亚型的分支间CTL交叉识别程度。用感染了表达源自HIV-1 B分支的HIV-1 env、gag、pol和nef基因的重组痘苗病毒载体的自体PBMC在体外刺激新鲜分离的PBMC。19名HIV-1血清阳性受试者中有13名引发了显著的B分支Env gp160LAI CD8+ CTL反应，他们对C92BR025分支Env gp160也表现出相当水平的CTL交叉反应性。其中9名个体对A92UG037分支Env gp160也表现出广泛的分支间CTL交叉识别。两名HLA I类B7供体对B Env gp160MN的分支内CTL反应检测不到，而对B(LAI)分支内以及A和C分支间Env gp160产生了显著的CTL交叉反应性。这些观察结果强调了个体的HLA背景在确定对自然HIV-1感染以及推测对疫苗的免疫反应模式中的核心重要性。研究的5名供体对A92UG037分支Gag p55、Pol和/或Nef抗原也表现出广泛的CTL交叉反应性。总之，本研究表明在HIV-1感染早期，对高度不同的HIV-1 Env gp160亚型存在相当程度的CD8+ CTL交叉识别。这些发现表明基于单一分支且能诱导广泛交叉分支免疫的HIV-1疫苗可能在不同地理区域具有实用性。
