Seattle Children's Research Institute, Seattle, Washington, United States of America.
Department of Pediatrics, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2021 Apr 29;16(4):e0240495. doi: 10.1371/journal.pone.0240495. eCollection 2021.
RATIONALE/STUDY DESIGN: A major challenge in the development of HIV vaccines is finding immunogens that elicit protection against a broad range of viral strains. Immunity to a narrow range of viral strains may protect infants of HIV-infected women or partners discordant for HIV. We hypothesized that immunization to the relevant viral variants could be achieved by exposure to infectious virus during prophylaxis with antiretroviral drugs. To explore this approach in an animal model, macaques were exposed to live virus (SIVmne or HIV-2287) during prophylaxis with parenteral tenofovir and humoral and cellular immune responses were quantified. Subsequently, experimental animals were challenged with homologous virus to evaluate protection from infection, and if infection occurred, the course of disease was compared to control animals. Experimental animals uninfected with SIVmne were challenged with heterologous HIV-2287 to assess resistance to retroviral infection.
METHODOLOGY/PRINCIPAL FINDINGS: Juvenile female Macaca nemestrina (N = 8) were given ten weekly intravaginal exposures with either moderately (SIVmne) or highly (HIV-2287) pathogenic virus during tenofovir prophylaxis. Tenofovir protected all 8 experimental animals from infection, while all untreated control animals became infected. Specific non-neutralizing antibodies were elicited in blood and vaginal secretions of experimental animals, but no ELISPOT responses were detected. Six weeks following the cessation of tenofovir, intravaginal challenge with homologous virus infected 2/4 (50%) of the SIVmne-immunized animals and 4/4 (100%) of the HIV-2287-immunized animals. The two SIVmne-infected and 3 (75%) HIV-2287-infected had attenuated disease, suggesting partial protection.
CONCLUSIONS/SIGNIFICANCE: Repeated exposure to SIVmne or HIV-2287, during antiretroviral prophylaxis that blocked infection, induced binding antibodies in the blood and mucosa, but not neutralizing antibodies or specific cellular immune responses. Studies to determine whether antibodies are similarly induced in breastfeeding infants and sexual partners discordant for HIV infection and receiving pre-exposure antiretroviral prophylaxis are warranted, including whether these antibodies appear to confer partial or complete protection from infection.
背景/研究设计：在 HIV 疫苗开发中，一个主要的挑战是寻找能够诱导针对广泛病毒株的保护的免疫原。对病毒株的窄范围免疫可能会保护 HIV 感染妇女的婴儿或 HIV 不一致的伴侣。我们假设通过在抗逆转录病毒药物预防中接触传染性病毒，可以实现针对相关病毒变体的免疫接种。为了在动物模型中探索这种方法，用猴免疫缺陷病毒（SIVmne 或 HIV-2287）暴露于接受预防性使用的注射用替诺福韦的猕猴中，并定量评估体液和细胞免疫反应。随后，用同源病毒对实验动物进行攻击，以评估对感染的保护作用，如果发生感染，则将疾病过程与对照动物进行比较。未感染 SIVmne 的实验动物用异源 HIV-2287 进行攻击，以评估对逆转录病毒感染的抵抗力。
方法/主要发现：8 只未成年雌性猕猴（N=8）在接受替诺福韦预防性治疗的同时，每周接受 10 次阴道内中度（SIVmne）或高度（HIV-2287）致病性病毒暴露。替诺福韦完全保护所有 8 只实验动物免受感染，而所有未接受治疗的对照动物均被感染。在实验动物的血液和阴道分泌物中诱导了特异性的非中和抗体，但未检测到 ELISPOT 反应。替诺福韦治疗停止后 6 周，用同源病毒进行阴道内攻击，感染了 4/4（100%）接受 HIV-2287 免疫的动物中的 2/4（50%）SIVmne 免疫的动物。2 只 SIVmne 感染和 3 只（75%）HIV-2287 感染的动物疾病减轻，表明存在部分保护。
结论/意义：在阻止感染的抗逆转录病毒预防过程中，反复接触 SIVmne 或 HIV-2287 诱导了血液和黏膜中的结合抗体，但未诱导中和抗体或特异性细胞免疫反应。需要进行研究以确定在接受暴露前抗逆转录病毒预防的哺乳期婴儿和 HIV 不一致的性伴侣中是否同样诱导了这些抗体，包括这些抗体是否似乎提供了部分或完全免受感染的保护。
