Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages.

Monocyte/macrophages (M/M) are important targets for HIV in the body, and represent the majority of cells infected by the virus in some body compartments such as the central nervous system (CNS). M/M can be different from T-lymphocytes in terms of surface antigens, cell replication and drug metabolism. Thus, we evaluated, in M/M and in T-lymphocytes, the pattern of viral inhibition induced by various anti-HIV drugs, and assessed some of the mechanisms of action related to such antiviral activity. Inhibitors of HIV binding on CD4 receptors have similar activity in M/M and T-lymphocytes, while AZT and other dideoxynucleosides (ddN) are in general more active against HIV in M/M than in T-lymphocytes. This phenomenon can be related to the increased ratio in M/M of ddN-triphosphate/deoxynucleoside-triphosphate, and can at least in part explain the ability of zidovudine and didanosine in improving neurological dysfunctions in AIDS patients. Moreover, the antiviral activity of AZT (but not of other ddN- or HIV-binding inhibitors) is potently enhanced by cytokines like granulocyte-macrophage colony stimulating factor (GM-CSF) in M/M, while anti-HIV activity of TIBO compounds in M/M is not down-modulated by GM-CSF and other cytokines. Finally, non-toxic concentrations of adriamycin, an anticancer drug reported to be active against DNA viruses, can inhibit HIV replication in M/M (but not in T-lymphocytes). Taken together, these results suggest that M/M are selective targets for HIV with peculiarities different from those of T-lymphocytes. Thus, promising anti-HIV compounds should be evaluated both in T-cells and in M/M before reaching clinical trials. This may help in selecting drugs with good chances of being effective in patients with HIV-related disease.     

Rationale for the Use of Immunotoxins in the Treatment of HIV-infected Humans

Abstract

The first step in the replication of human immunodeficiency virus (HIV) is selective binding of the envelope glycoprotein (gp120) to CD4 receptors on T cells or macrophages. After penetration in these cells, the genome of the virus is integrated in the human genome. HIV-infection causes depletion of CD4-positive cells resulting in a severe immunosuppression. It is believed that eliminating HIV-infected cells is crucial in limiting further reduction of CD4-positive cells and thus, preventing disease progression. The most commonly used drugs, such as zidovudine (AZT), appeared to be not completely effective. Therefore many investigators are searching for alternative treatment modalities. The use of immunotoxins (ITs) to eliminate HIV-infected cells is discussed.

ITs are chimeric molecules in which cell-binding ligands are coupled to toxins and can specifically eliminate undesired cells. The cell-binding carriers of anti-HIV ITs have been directed against different regions of the HIV envelope glycoprotein (gp120 and gp41) and surface antigens (e.g CD4, CD25). The ITs have been composed of different ribosome-inactivating proteins (RIPs) like pokeweed antiviral protein (PAP), Pseudomonas exotoxin (PE), Diphtheria toxin (DT), or ricin. In in vitro studies, several of these ITs have been shown to be effective and specific in killing acute and persistently HIV-infected cells. The ITs were effective at concentrations (ID50 range from 10^-9 M to 10^-12 M) that were not toxic to uninfected cells or cells without the antigen. The IT CD4(178)PE40, a fusion protein directed against the CD4 binding site of gp120, has been investigated in two in vivo trials. The results were disappointing considering die antiviral activity in vitro. This was thought to be due to the rapid clearance of the IT and the differential resistance of clinical HIV isolates. Use of a panel of ITs is likely to be more effective because multiple approaches cover the intrinsic variability of HIV and the presence of IT-resistant or latently infected cells, as well as the blocking presence of neutralizing anti-HIV antibodies and the immunogenicity of most ITs.

It may be possible to control the virus completely with a panel of ITs in combination with other antiviral or immunosuppressive agents such as RT inhibitors (e.g AZT), interferon α, or cyclosporine. More research will be necessary to develop such a combined therapy.     

基于生物电子等排原理的核苷类HIV-1逆转录酶抑制剂研究进展

核苷类HIV逆转录酶抑制剂(NRTIs)作为逆转录酶的特异性抑制剂,是临床最早应用的一类抗HIV药物,至今仍发挥着重要的作用。NRTIs的应用有效地缓解症状,延长病程,对治疗AIDS有很好的效果。然而由于耐药毒株及毒副作用的出现,NRTIs的疗效受到很大限制,因此研发高效、低毒、耐突变的新型NRTIs仍然是目前的热点之一。通过生物电子等排原理对核苷类药物进行广泛的结构修饰是获得高效、低毒、具有较高生物利用度的新型药物的有效途径。本文综述了该领域的研究进展。     

Anti-HIV agents targeting the interaction of gp120 with the cellular CD4 receptor

Perhaps one of the most effective approaches to prevent and inhibit viral infections is to block host cell receptors that are used by viruses to gain cell entry. Major advances have been made over the past decade in the understanding of the molecular mechanism of HIV entry into target cells. A crucial step in this entry process is the interaction of the external HIV envelope glycoprotein, gp120, with the cellular CD4 receptor molecule. This binding step represents a potential target for new antiviral agents, and current efforts to develop safe and effective HIV entry inhibitors are focused on natural ligands and/or monoclonal antibodies that interfere with gp120/CD4 interaction. Also, small synthetic compounds obtained either by high-throughput screening of large compound libraries or by structure-guided rational design have recently entered the antiretroviral arena. In this review, the anti-HIV activity of novel entry inhibitors targeting gp120/CD4 interaction is outlined, and special attention is given to the cyclotriazadisulfonamide compounds, which are the most specific CD4-targeted antiviral drugs described so far.     

Anti-HIV agents targeting the interaction of gp120 with the cellular CD4 receptor

Perhaps one of the most effective approaches to prevent and inhibit viral infections is to block host cell receptors that are used by viruses to gain cell entry. Major advances have been made over the past decade in the understanding of the molecular mechanism of HIV entry into target cells. A crucial step in this entry process is the interaction of the external HIV envelope glycoprotein, gp120, with the cellular CD4 receptor molecule. This binding step represents a potential target for new antiviral agents, and current efforts to develop safe and effective HIV entry inhibitors are focused on natural ligands and/or monoclonal antibodies that interfere with gp120/CD4 interaction. Also, small synthetic compounds obtained either by high-throughput screening of large compound libraries or by structure-guided rational design have recently entered the antiretroviral arena. In this review, the anti-HIV activity of novel entry inhibitors targeting gp120/CD4 interaction is outlined, and special attention is given to the cyclotriazadisulfonamide compounds, which are the most specific CD4-targeted antiviral drugs described so far.     

新型抗艾滋病药物——HIV进入抑制剂的研究进展

HIV与靶细胞融合的过程是药物干预的重要环节。融合过程主要由H IV包被蛋白表面亚基gp120和跨膜亚基gp41介导。H IV gp120与靶细胞上的CD4分子和辅助受体(趋化因子受体CCR5或CXCR4等)结合,导致gp41的构型发生改变,启动病毒包膜与靶细胞膜的融合。在融合过程中,病毒和靶细胞上的这些蛋白和受体均可作为药物的作用靶点,寻找抑制H IV进入靶细胞的药物用来治疗H IV感染和艾滋病。作用于gp41的肽类药物T-20已被美国FDA批准上市,表明继逆转录酶抑制剂和蛋白酶抑制剂后,H IV进入抑制剂作为第3类抗H IV药物开始在临床上应用。作为一种新机制的抗H IV药物,H IV进入抑制剂单独或与逆转录酶抑制剂和蛋白酶抑制剂联合应用,将有助于提高药物的疗效,降低毒副作用,并可望挽救对现有抗H IV药物耐药的艾滋病病人的生命。该文综述了近年来H IV进入抑制剂的研究进展。