Laboratory of Immunoregulation, Division of Viral Products, Office of Vaccines, Center for Biologics, Food and Drug Administration, Silver Spring, Maryland, United States of America.
Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, Maryland, United States of America.
PLoS One. 2020 Mar 4;15(3):e0228163. doi: 10.1371/journal.pone.0228163. eCollection 2020.
Anti-retroviral therapy (ART) has been highly successful in controlling HIV replication, reducing viral burden, and preventing both progression to AIDS and viral transmission. Yet, ART alone cannot cure the infection. Even after years of successful therapy, ART withdrawal leads inevitably to viral rebound within a few weeks or months. Our hypothesis: effective therapy must control both the replicating virus pool and the reactivatable latent viral reservoir. To do this, we have combined ART and immunotherapy to attack both viral pools simultaneously. The vaccine regimen consisted of DNA vaccine expressing SIV Gag, followed by a boost with live attenuated rubella/gag vectors. The vectors grow well in rhesus macaques, and they are potent immunogens when used in a prime and boost strategy. We infected rhesus macaques by high dose mucosal challenge with virulent SIVmac251 and waited three days to allow viral dissemination and establishment of a reactivatable viral reservoir before starting ART. While on ART, the control group received control DNA and empty rubella vaccine, while the immunotherapy group received DNA/gag prime, followed by boosts with rubella vectors expressing SIV gag over 27 weeks. Both groups had a vaccine "take" to rubella, and the vaccine group developed antibodies and T cells specific for Gag. Five weeks after the last immunization, we stopped ART and monitored virus rebound. All four control animals eventually had a viral rebound, and two were euthanized for AIDS. One control macaque did not rebound until 2 years after ART release. In contrast, there was only one viral rebound in the vaccine group. Three out of four vaccinees had no viral rebound, even after CD8 depletion, and they remain in drug-free viral remission more than 2.5 years later. The strategy of early ART combined with immunotherapy can produce a sustained SIV remission in macaques and may be relevant for immunotherapy of HIV in humans.
抗逆转录病毒疗法（ART）在控制 HIV 复制、降低病毒载量以及预防艾滋病进展和病毒传播方面取得了巨大成功。然而，ART 本身并不能治愈感染。即使经过多年成功的治疗，停止 ART 治疗后，病毒会在数周或数月内不可避免地反弹。我们的假设是：有效的治疗必须控制复制病毒池和可激活的潜伏病毒库。为此，我们将 ART 与免疫疗法结合起来，同时攻击这两个病毒池。疫苗方案包括表达 SIV Gag 的 DNA 疫苗，随后用活减毒风疹/ gag 载体加强。载体在恒河猴中生长良好，当用于初次免疫和加强免疫策略时，它们是有效的免疫原。我们用高剂量黏膜挑战感染恒河猴，用 SIVmac251 感染病毒，然后等待三天，让病毒传播并建立可激活的病毒库，然后开始 ART。在接受 ART 的同时，对照组接受对照 DNA 和空风疹疫苗，而免疫治疗组接受 DNA/gag 初次免疫，然后在 27 周内用表达 SIV gag 的风疹载体加强免疫。两组均对风疹疫苗产生了“免疫效果”，并产生了针对 Gag 的抗体和 T 细胞。最后一次免疫接种后 5 周，我们停止 ART 并监测病毒反弹。所有四只对照组动物最终都出现病毒反弹，其中两只因 AIDS 而被安乐死。一只对照组猴子在停止 ART 治疗后 2 年才出现病毒反弹。相比之下，疫苗组只有一次病毒反弹。四分之三的疫苗接种者在 CD8 耗尽后没有病毒反弹，并且在 2 年半多后仍处于无药物病毒缓解状态。早期 ART 结合免疫疗法的策略可以使恒河猴体内的 SIV 持续缓解，这可能与人类 HIV 的免疫治疗相关。
