Negri Donatella, Blasi Maria, LaBranche Celia, Parks Robert, Balachandran Harikrishnan, Lifton Michelle, Shen Xiaoying, Denny Thomas, Ferrari Guido, Vescio Maria Fenicia, Andersen Hanne, Montefiori David C, Tomaras Georgia D, Liao Hua-Xin, Santra Sampa, Haynes Barton F, Klotman Mary E, Cara Andrea
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA; Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy.
Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Mol Ther. 2016 Nov;24(11):2021-2032. doi: 10.1038/mt.2016.123. Epub 2016 Jun 21.
The design of an effective HIV-1 vaccine remains a major challenge. Several vaccine strategies based on viral vectors have been evaluated in preclinical and clinical trials, with largely disappointing results. Integrase defective lentiviral vectors (IDLV) represent a promising vaccine candidate given their ability to induce durable and protective immune responses in mice after a single immunization. Here, we evaluated the immunogenicity of a SIV-based IDLV in nonhuman primates. Six rhesus monkeys were primed intramuscularly with IDLV-Env and boosted with the same vector after 1 year. A single immunization with IDLV-Env induced broad humoral and cellular immune responses that waned over time but were still detectable at 1 year postprime. The boost with IDLV-Env performed at 1 year from the prime induced a remarkable increase in both antibodies and T-cell responses. Antibody binding specificity showed a predominant cross-clade gp120-directed response. Monkeys' sera efficiently blocked anti-V2 and anti-CD4 binding site antibodies, neutralized the tier 1 MW965.26 pseudovirus and mediated antibody-dependent cellular cytotoxicity (ADCC). Durable polyfunctional Env-specific T-cell responses were also elicited. Our study demonstrates that an IDLV-Env-based vaccine induces functional, comprehensive, and durable immune responses in Rhesus macaques. These results support further evaluation of IDLV as a new HIV-1 vaccine delivery platform.
设计一种有效的HIV-1疫苗仍然是一项重大挑战。几种基于病毒载体的疫苗策略已在临床前和临床试验中进行了评估，结果大多令人失望。整合酶缺陷型慢病毒载体（IDLV）因其能够在单次免疫后在小鼠中诱导持久且具有保护性的免疫反应，成为一种有前景的疫苗候选物。在此，我们评估了一种基于猴免疫缺陷病毒（SIV）的IDLV在非人灵长类动物中的免疫原性。6只恒河猴肌肉注射IDLV-Env进行初次免疫，并在1年后用相同载体进行加强免疫。单次注射IDLV-Env可诱导广泛的体液免疫和细胞免疫反应，这些反应随时间减弱，但在初次免疫后1年仍可检测到。在初次免疫1年后进行的IDLV-Env加强免疫显著增强了抗体和T细胞反应。抗体结合特异性显示出主要针对跨亚型gp120的反应。猴子血清有效阻断了抗V2和抗CD4结合位点抗体，中和了1级MW965.26假病毒，并介导了抗体依赖性细胞毒性（ADCC）。还引发了持久的多功能Env特异性T细胞反应。我们的研究表明，基于IDLV-Env的疫苗可在恒河猴中诱导功能性、全面且持久的免疫反应。这些结果支持进一步评估IDLV作为一种新的HIV-1疫苗递送平台。
