抗体依存性感染増強
A study conducted by Modhiran et al. attempted to explain how non-neutralizing antibodies down-regulate the immune response in the host cell through the Toll-like receptor signaling pathway. Toll-like receptors are known to recognize extra- and intracellular viral particles and to be a major basis of the cytokines production. In vitro experiments showed that the inflammatory cytokines and type 1 interferon production were reduced when the ADE-dengue virus complex bound to the Fc receptor of THP-1 cells. This can be explained by both a decrease of Toll-like receptor production and a modification of its signaling pathway. On one hand, an unknown protein induced by the stimulated Fc receptor reduces the Toll-like receptor transcription and translation, which reduces the capacity of the cell to detect viral proteins. On the other hand, many proteins (TRIF, TRAF6, TRAM, TIRAP, IKKα, TAB1, TAB2, NF-κB complex) involved in the Toll-like receptor signaling pathway are down-regulated, which led to a decrease of the cytokine production. Two of them, TRIF and TRAF6, are respectively down-regulated by 2 proteins SARM and TANK up-regulated by the stimulated Fc receptors.
To illustrate the phenomenon of ADE, consider the following example: an epidemic of dengue fever occurred in Cuba, lasting from 1977 to 1979. The infecting serotype was dengue virus-1. This epidemic was followed by two more outbreaks of dengue fever—one in 1981 and one in 1997; dengue virus-2 was the infecting serotype in both of these later epidemics. 205 cases of dengue hemorrhagic fever and dengue shock syndrome occurred during the 1997 outbreak, all in people older than 15 years. All but three of these cases were demonstrated to have been previously infected by the dengue virus-1 serotype during the epidemic of 1977–1979. Furthermore, people who had been infected with dengue virus-1 during the 1977-79 outbreak and secondarily infected with dengue virus-2 in 1997 had a 3-4 fold increased probability of developing severe disease than those secondarily infected with dengue virus-2 in 1981. This scenario can be explained by the presence of neutralizing heterotypic IgG antibodies in sufficient titers in 1981, the titers of which had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.
ADE of infection has also been reported in HIV. Like dengue virus, non-neutralizing level of antibodies have been found to enhance the viral infection through interactions of the complement system and receptors. The increase in infection has been reported to be over 350 fold which is comparable to ADE in other viruses like dengue virus. ADE in HIV can be complement-mediated or Fc receptor-mediated. Complements in the presence of HIV-1 positive sera have been found to enhance the infection of MT-2 T-cell line. The Fc-receptor mediated enhancement was reported when HIV infection was enhanced by sera from HIV-1 positive guinea pig enhanced the infection of peripheral blood mononuclear cells without the presence of any complements. Complement component receptors CR2, CR3 and CR4 have been found to mediate this Complement-mediated enhancement of infection. The infection of HIV-1 leads to activation of complements. Fragments of these complements can assist viruses with infection by facilitating viral interactions with host cells that express complement receptors. The deposition of complement on the virus brings the gp120 protein close to CD4 molecules on the surface of the cells, thus leading to facilitated viral entry. Viruses pre-exposed to non-neutralizing complement system have also been found to enhance infections in interdigitating dendritic cells. Opsonized viruses have not only shown enhanced entry but also favorable signaling cascades for HIV replication in interdigitating dendritic cells.
HIV-1 has also shown enhancement of infection in HT-29 cells when the viruses were pre-opsonized with complements C3 and C9 in seminal fluid. This enhanced rate of infection was almost 2 times greater than infection of HT-29 cells with virus alone. Subramanian et al., reported that almost 72% of serum samples out of 39 HIV positive individuals contained complements that were known to enhance the infection. They also suggested that the presence of neutralizing antibody or antibody-dependent cellular cytotoxicity-mediating antibodies in the serum contains infection-enhancing antibodies. The balance between the neutralizing antibodies and infection-enhancing antibodies changes as the disease progresses. During advanced stages of the disease the proportion of infection-enhancing antibodies are generally higher than neutralizing antibodies. Increase in viral protein synthesis and RNA production have been reported to occur during the complement-mediated enhancement of infection. Cells that are challenged with non-neutralizing levels of complements have been found have accelerated release of reverse transcriptase and the viral progeny. The interaction of anti-HIV antibodies with non-neutralizing complement exposed viruses also aid in binding of the virus and the erythrocytes which can lead to more efficient delivery of viruses to the immune-compromised organs.
ADE in HIV has raised questions about the risk of infections to volunteers who have taken sub-neutralizing levels of vaccine just like any other viruses that exhibit ADE. Gilbert et al., in 2005 reported that there was no ADE of infection when they used rgp120 vaccine in phase 1 and 2 trials. It has been emphasized that much research needs to be done in the field of the immune response to HIV-1, information from these studies can be used to produce a more effective vaccine.
抗体はウイルスと相互作用して、ウイルスが宿主細胞のエントリーレセプターに付着するのを防ぐ必要がある。しかし、このプロセスは、宿主細胞への感染を防ぐ代わりに、ウイルスの免疫細胞への感染を促進し、ADEを引き起こす可能性がある。ウイルスと結合した後、抗体は、特定の免疫細胞に発現するFcまたは補体受容体と相互作用する。これらの受容体は、免疫細胞によるウイルス-抗体複合体の内在化を促進し、これにより通常はウイルスは破壊される。しかし、ウイルスが抗体複合体から逃れ、分解を避けて免疫細胞内で複製サイクルを開始する可能性も存在する。これは、ウイルスが低親和性の抗体と結合している場合に起こりうる。
細胞内でのウイルスの生存率が高まる現象を説明するものには、いくつかの可能性がある。
ある血清型のウイルスに対する抗体が、異なる血清型のウイルスに結合する。この結合は、ウイルスが宿主細胞に付着するのを中和するためのものであるが、ウイルス-抗体複合体は、免疫細胞上のFc領域の抗体受容体(FcγR)にも結合する。細胞はウイルス破壊のためにウイルスを内在化するが、ウイルスはそこから逃れ、複製サイクルを開始する。
ある血清型のウイルスに対する抗体が、異なる血清型のウイルスに結合し、補体系の古典経路を活性化する。補体カスケードシステムは、抗体を介してウイルス表面タンパク質に結合したC1q複合体と結合し、C1q複合体は細胞に存在するC1q受容体と結合して、ウイルスと細胞を近づけ、特定のウイルス受容体がウイルスと結合して感染が始まる。 このメカニズムは、in vitro ではエボラウイルス、in vivo ではいくつかのフラビウイルスで示されている。
ウイルスに対する抗体がウイルスを充分に中和できない場合、不完全中和ウイルス-抗体複合体を形成する。マクロファージなどの免疫細胞に貪食されると、抗体との結合が不充分なため、複合体からウイルスが放出される。これは、ファゴソームが酸性化し、最終的にリソソームと融合する際に発生する。脱出したウイルスは、細胞内で複製サイクルを開始し、ADEの引き金となる。