The use of Envelope for HIV therapeutics: from vaccines to co-receptors

The Envelope protein (Env) of the human immunodeficiency virus (HIV) has been a primary target and tool for antiviral drug and vaccine development since the discovery of the virus. The study of Env has led to a knowledge of the virus life-cycle, structure and immunological response that has helped lead HIV-directed therapeutic strategies in new, unexpected directions. In particular, the discovery of chemokine receptors as the HIV co-receptors in 1996 is allowing a new generation of antiviral and vaccine candidates to be developed that are based on the ability to block the function of Env in mediating viral entry. This review discusses the primary roles of Env throughout its course of investigation as a tool for vaccine development and as a target for drug screening, emphasising the recent role of Env in the discovery and exploration of the co-receptors. The use of gp120/chemokine binding assays, chemokine receptor structure-function studies and co-receptor polymorphisms are discussed in the context of the development of high-throughput screening assays, creation of immunogens with enhanced vaccine potential and targeting of the co-receptors CCR5 and CXCR4 by small-molecule inhibitors of HIV entry.     

Cytokine and chemokine based control of HIV infection and replication

HIV infects and propagates into CD4+ T lymphocytes and macrophages, although many other cell types play an important role in virus spreading and pathogenesis. In addition to regulatory viral proteins, the cytokine network has early been implicated as a major controller of the plastic capacity of HIV to spread productively or rather remain silently integrated in the chromosomes of infected cells. The recent discovery of CCR5 and CXCR4 as essential entry co-receptors together with CD4 has highlighted a novel and potentially important step in the pharmacological hunt for more effective antiviral agents. In addition to regulate HIV expression and replication, several cytokines have demonstrated the capacity of up- or down-modulating chemokine receptors including CCR5 and CXCR4 with the consequence of influencing the susceptibility of T cells and macrophages to HIV infection. Pharmacological agents such as pertussis toxin B-oligomer have demonstrated HIV suppressive effects via non competitive binding of CCR5, whereas interferons or interleukin-16 (IL-16) can prevent post-entry steps in HIV expression. At the clinical level, several cytokines or their receptors are useful markers for monitoring disease progression and its consequence on the immune system. Cytokine-based therapy represents a realistic complementary approach to traditional antiretroviral therapy potentially capable of restoring important adaptive or innate immune functions ultimately curtailing HIV spreading and its consequences on the immune system, as exemplified by the experimental clinical use of IL-2.     

趋化因子及其受体与艾滋病的研究进展*

HIV感染和艾滋病(AIDS)是严重危害人类健康的疾病,用抗HIV药物可以明显延缓AIDS进程降低死亡率。趋化因子是一系列结构相似的具有趋化功能的细胞因子。趋化因子受体CXCR4和CCR5是HIV感染重要的辅助受体,这一发现为进一步了解HIV感染机制和AIDS治疗提供了新的思路。现主要综述趋化因子及其受体的结构和功能,以及它们在抗HIV感染方面的作用。     

HIV co-receptor inhibitors as novel class of anti-HIV drugs

Entry inhibitors constitute a new class of drugs to treat infection by human immunodeficiency virus type 1 (HIV-1). The first member of this class, enfuvirtide, previously known as T-20 and targeting gp41, has now been licensed for therapeutic use. Several other entry inhibitors are in various stages of pre-clinical or clinical development. In this review we focus on the chemokine receptor inhibitors targeting CCR5 and CXCR4 that are the main HIV co-receptors for viral entry.     

The therapeutic potential of CXCR4 antagonists in the treatment of HIV

Since the identification of the chemokine receptors CXCR4 and CCR5 as co-receptors for HIV-1 entry, several antagonists against these receptors have been synthesised. A highly selective CXCR4 antagonist, T22, and its downsized analogues T140 and TC14012, which inhibit X4-HIV-1 infection through their specific binding to CXCR4, have been identified. Besides T22 analogues, several other CXCR4 antagonists have been reported, such as AMD3100, ALX40-4C, KRH-1120 and AMD8664. Discovery of entry inhibitors, such as chemokine antagonists, may lead to the development of a new generation of antiHIV agents, since these inhibitors are thought to be useful for the clinical treatment of HIV-1-infected patients, especially at the late stage of treatment for AIDS patients developing multi-drug-resistant strains. In this review, recent research into CXCR4 antagonists in comparison with development of other antagonists is summarised.     

Genetic Knockouts Suggest a Critical Role for HIV Co-Receptors in Models of HIV gp120-Induced Brain Injury

Infection with HIV-1 frequently affects the brain and causes NeuroAIDS prior to the development of overt AIDS. The HIV-1 envelope protein gp120 interacts with host CD4 and chemokine co-receptors to initiate infection of macrophages and lymphocytes. In addition, the virus or fragments of it, such as gp120, cause macrophages to produce neurotoxins and trigger neuronal injury and apoptosis. Moreover, the two major HIV co-receptors, the chemokine receptors CCR5 and CXCR4, serve numerous physiological functions and are widely expressed beyond immune cells, including cells in the brain. Therefore, HIV co-receptors are poised to play a direct and indirect part in the development of NeuroAIDS. Although rodents are not permissive to infection with wild type HIV-1, viral co-receptors - more than CD4 - are highly conserved between species, suggesting the animals can be suitable models for mechanistic studies addressing effects of receptor-ligand interaction other than infection. Of note, transgenic mice expressing HIV gp120 in the brain share several pathological hallmarks with NeuroAIDS brains. Against this background, we will discuss recently completed or initiated, ongoing studies that utilize HIV co-receptor knockout and viral gp120-transgenic mice as models for in vitro and in vivo experimentation in order to address the potential roles of HIV gp120 and its co-receptors in the development of NeuroAIDS.     

HIV-1 (co)receptors: implications for vaccine and therapy design

The ultimate aim of therapy or vaccine design against HIV is to eliminate ongoing virus replication or prevent HIV infection. The task at hand is daunting given the wide array of HIV variants circulating and the immense degree of variation found within the virus, especially in the envelope glycoprotein. HIV utilizes the CD4 receptor and a range of 7 transmembrane chemokine coreceptors for cell entry, specifically CCR5 and CXCR4. These receptors provide a number of targets for therapy design, however, the finding that multiple receptors allow for viral entry suggest that targeting one may cause the virus to swirch to using another receptor. The molecular interactions directing coreceptor usage are complex and can involve the same modifications associated with escape from the effect of neutralizing antibodies (NAbs), indicating that they are not unrelated and can in all liklihood impact on each other. Furthermore, a large array of other receptors, other than CD4, CCR5 and/or CXCR4 can interact with HIV with consequences for HIV tranmssion as well as disease progression.     

以趋化因子受体为靶点的抗HIV药物研究进展

趋化因子受体是HIV进入宿主细胞的共受体,特别是CCR5和CXCR4在HIV进入免疫细胞过程中起着重要作用。以趋化因子受体为靶点的新型抗艾滋病药物的设计与开发已成为抗艾滋病领域研究的一个热点课题。本文对近期抗HIV-1趋化因子受体(CCR5和CXCR4)拮抗剂的研究进展进行综述。     

Current drug design of anti-HIV agents through the inhibition of C-C chemokine receptor type 5

Human immunodeficiency virus (HIV) is the responsible causal agent of acquired immunodeficiency syndrome (AIDS), a condition in humans in which the immune system begins to fail, allowing the entry of opportunistic infections. HIV infection in humans is considered pandemic by the World Health Organization (WHO). HIV needs to use a protein as a co-receptor to enter its target cells. Several chemokine receptors can in principle act as viral co-receptors, but the chemokine (C-C motif) receptor 5 (CCR5) is likely the most physiologically important co-receptor during natural infection. For this reason the development of new CCR5 inhibitors like anti-HIV agents, constitutes a challenge for the scientific community. The present review will focus on the current state of the design of novel anti-HIV drugs, and how the existing computer aided-drug design methodologies, have been effective in the search of new anti-HIV agents. In addition, a QSAR model based on substructural descirptors is presented as a rapid, rational and promising alternative for the discovery of anti-HIV agents through the inhibition of the CCR5.     

Double doors and gatekeepers: HIV co-receptors and chemokines

The identification of CD4 as the HIV receptor immediately triggered a search for the development of novel therapeutic agents aimed at blocking receptor binding. Initial experimental approaches to this problem failed, but led to the observation that one or more other receptors for HIV, or co-receptors, must be involved in the entry of the virus in cells. In 1996 evidence was reported of a second viral receptor, already known under several names and renamed "fusin." Shortly thereafter the CCR5 molecule was identified as a co-receptor for the second type of HIV strain. This second discovery left no doubts: the second receptor for the virus encompassed at least two members of the chemokine receptor family. The identification of these co-receptors has led to several important new observations about HIV, including the fact that chemokines are potent in vitro inhibitors of viral replication, at least in T lymphocytes; however, there is still little information on their role in vivo. Nevertheless, unlike chemokines, the role of chemokine receptors in vivo has already emerged as being of substantial importance.     

Circular CCR5 peptide conjugates and uses thereof (WO2008074895)

Background: Several new strategies targeting HIV infection aim to inhibit virus entry by blocking the chemokine receptor CCR5 used by macrophage tropic strains associated with early infection. The current application uses virus-like particles as a support to present CCR5 peptide antigens. Objectives: The virus-like particle (VLP)–CCR5 composition aims to function as either a preventative and/or therapeutic vaccine inducing durable autoantibodies that can block CCR5 and prevent HIV entry or attenuate disease progression. Methods: The novelty of the current application lies in the chemical conjugation of circularised peptide antigens to VLPs, primarily the CCR5 N-terminal domain alone but also including the first extracellular loop (ECL-1). Immunised mice and rabbits generated antibodies that recognised native CCR5 and inhibited entry of pseudotype viruses bearing envelope glycoproteins from diverse primary strains in vitro. Results/conclusions: Further work is required to assess the in vivo therapeutic potential of these CCR5 compositions. As therapeutic vaccines and/or preventative vaccines, the potential for selecting CXCR4 tropic virus populations associated with disease progression will need to be considered in addition to the broader consequences of targeting a cellular antigen involved in innate immunity.     

Small molecules anti-HIV therapeutics targeting CXCR4

HIV cellular entry is a multistep process that requires the interaction of a viral envelope glycoprotein (gp120) and a host receptor (CD4) followed by binding to a co-receptor. The CC-chemokine receptor 5 (CCR5) and CXC-chemokine receptor 4 (CXCR4) have been identified as the major HIV co-receptors and therefore are promising targets for the development of new anti-HIV drugs. CXCR4 is also involved in several diseases such as angiogenesis, metabolic and neurological disorders, rheumatoid arthritis and in different forms of metastatic cancer. Herein, we present a review focusing on small molecule CXCR4 antagonists. These compounds are divided into 11 classes that include cyclic penta- and tetrapeptides, diketopiperazine mimetics, bicyclams, non-bicyclams, tetrahydroquinolines, thiazolylisothiourea derivatives, benzodiazepines, alkyl amine analogs and non-peptides derivatives, dipicolylamine-zinc(II) complexes, ampelopsin and distamycin analogs. The most advanced CXCR4 antagonists documented are bicyclam derivatives, which are specific CXCR4 antagonists and exhibit potency in the nanomolar range. Further development of selective CXCR4 antagonists continues to be crucial for the design of second generation of anti-HIV drugs. We aim to provide a comprehensive summary of diverse structural templates that could be useful for optimization and discovery of novel CXCR4 antagonists.