Tulane National Primate Research Center, Tulane University School of Medicine, Covington, LA, USA.
FASEB J. 2021 Feb;35(2):e21282. doi: 10.1096/fj.202002235R.
Cellular viral reservoirs are rapidly established in tissues upon HIV-1/SIV infection, which persist throughout viral infection, even under long-term antiretroviral therapy (ART). Specific integrins are involved in the homing of cells to gut-associated lymphoid tissues (GALT) and inflamed tissues, which may promote the seeding and dissemination of HIV-1/SIV to these tissue sites. In this study, we investigated the efficacy of prophylactic integrin blockade (α4β7 antibody or α4β7/α4β1 dual antagonist TR-14035) on viral infection, as well as dissemination and seeding of viral reservoirs in systemic and lymphoid compartments post-SIV inoculation. The results showed that blockade of α4β7/α4β1 did not decrease viral infection, replication, or reduce viral reservoir size in tissues of rhesus macaques after SIV infection, as indicated by equivalent levels of plasma viremia and cell-associated SIV RNA/DNA to controls. Surprisingly, TR-14035 administration in acute SIV infection resulted in consistently higher viremia and more rapid disease progression. These findings suggest that integrin blockade alone fails to effectively control viral infection, replication, dissemination, and reservoir establishment in HIV-1/SIV infection. The use of integrin blockade for prevention or/and therapeutic strategies requires further investigation.
细胞病毒库在 HIV-1/SIV 感染后迅速在组织中建立，并在病毒感染过程中持续存在，即使在长期抗逆转录病毒治疗 (ART) 下也是如此。特定的整合素参与细胞向肠道相关淋巴组织 (GALT) 和炎症组织的归巢，这可能促进 HIV-1/SIV 向这些组织部位的定植和传播。在这项研究中，我们研究了预防整合素阻断 (α4β7 抗体或 α4β7/α4β1 双重拮抗剂 TR-14035) 对 SIV 接种后病毒感染以及病毒库在全身和淋巴器官中的传播和定植的疗效。结果表明，阻断 α4β7/α4β1 并不能降低恒河猴 SIV 感染后血浆病毒血症和细胞相关 SIV RNA/DNA 的水平，从而降低病毒感染、复制或减少组织中的病毒库大小。令人惊讶的是，在急性 SIV 感染中给予 TR-14035 会导致 consistently higher viremia 和更快速的疾病进展。这些发现表明，单独使用整合素阻断不能有效控制 HIV-1/SIV 感染、复制、传播和库建立。整合素阻断用于预防和/或治疗策略的使用需要进一步研究。
