HIV-1 regulatory proteins: targets for novel drug development

Due to the development of HIV-1 resistance to current antiviral drugs and the known toxicity of many of these drugs, there is a clear need to identify and develop novel compounds for use in the treatment of HIV-1 infected patients. The HIV-1 regulatory proteins, Tat and Rev, are required for HIV-1 replication and therefore represent two important viral targets for drug development. Novel drugs that target these proteins would increase the number of available treatment strategies for HIV-1 infection. This could result in better combination therapies in which many different viral targets could be inhibited simultaneously, thereby decreasing the likelihood of selecting for drug-resistant viruses. This review outlines many of the ways that Tat and Rev can be targeted for drug development, describes recently reported lead compounds as inhibitors of these proteins and discusses strategies for implementing drug screens for identifying novel inhibitors.     

抗艾滋病药物研究的新靶点

目前,临床使用的抗艾滋病药物主要是逆转录酶抑制剂和蛋白酶抑制剂。由于这些药物的毒性和耐药性等问题日益严重,寻找抗艾滋病药物的新靶点已经成为当务之急。在细胞水平上对HIV病毒自身生活周期的研究发现了一些新的药物靶点,其中包括病毒自身生活周期所需的蛋白,宿主细胞内源性抗病毒因子及其他抗HIV-1感染的潜在靶标。本文对近年来研究中出现的新的抗艾滋病药物靶点作一综述。     

Regulatory and accessory HIV-1 proteins: potential targets for HIV-1 vaccines?

The HIV-1 regulatory proteins Tat and Rev and the accessory proteins Vpr, Vpu and Vif are essential for efficient viral replication, and their cytoplasmic production suggests that they should be processed for recognition by cytotoxic T lymphocytes. However, only limited data is available, evaluating the role of immune responses directed against these proteins in natural HIV-1 infection. Recent advances in the methods used for the characterization of HIV-1-specific cellular immune responses, including quantification of antigen-specific IFN-gamma production by ELISpot assay and flow-cytometry-based intracellular cytokine quantification, have allowed for a much more comprehensive assessment of virus-specific immune responses. Emerging data show that the regulatory and accessory proteins serve as important targets for HIV-1-specific T cell responses, and multiple CTL epitopes have been identified in functionally important regions of these proteins. Moreover, the use of autologous peptides have allowed for the detection of significantly stronger HIV-1-specific T cell responses in the more variable regulatory and accessory HIV-1 proteins Tat and Vpr. These data indicate that despite the small size of these proteins, regulatory and accessory proteins are targeted by cellular immune responses in natural HIV-1 infection and contribute importantly to the total HIV-1-specific CD8+ T cell response. A multi-component vaccine, with the inclusion of these proteins plus structural proteins remains the most promising choice for an effective AIDS vaccine.     

HIV-1 capsid protein and cyclophilin a as new targets for anti-AIDS therapeutic agents

The emergence of drug resistant mutations in current anti-HIV-1 drug regimens is an important determinant of the eventual drug failure. New drug development strategies that focus on either new targets or novel compounds are therefore critical for future effective viral suppression in HIV-1 infected individuals. Particularly, virus assembly and disassembly are attractive candidate processes for antiviral intervention. HIV-1 capsid (CA) protein and human cyclophilin A (CypA) play important roles in these processes, which consequently make them attractive targets of high priority. Inhibitors that target CA or CypA have been mainly divided into three classes: (1) compounds that specifically block capsid protein formation; (2) compounds that directly bind to the capsid and inhibit its assembly; and (3) compounds that bind to Cyp A and possibly inhibit the disassembly of capsid conical cores. Here, we give an overview of HIV-1 CA protein and Cyp A as new targets for potential anti-AIDS therapeutic agents.     

New developments in diketo-containing inhibitors of HIV-1 integrase

HIV-1 integrase is one of the three enzymes, which are critical for viral replication. It catalyzes the integration of the HIV genome into the cellular chromosome. Since there is no known human homolog to integrase, its inhibition is one of the most promising novel drug targets for anti-retroviral therapy with potential advantage over existing therapies. To date, numerous compounds with diverse structural features have been reported as integrase inhibitors, among which the diketo-containing inhibitors of HIV-1 integrase represent a major lead for anti-HIV drug development. The discovery of diketo acids plays an important role in validating integrase as a legitimate target for treatment of AIDS. In this review, we summarize several drug candidates in clinical trials and new diketo-containing inhibitors of HIV-1 integrase discovered recently.     

Problems and emerging approaches in HIV/AIDS vaccine development

According to recent estimates, 39.5 million people have been infected with HIV and 2.9 million have already died. The effect of HIV infection on individuals and communities is socially and economically devastating. Although antiretroviral drugs have had a dramatically beneficial impact on HIV-infected individuals who have access to treatment, it has had a negligible impact on the global epidemic. Therefore, the need for an efficacious HIV/AIDS vaccine remains the highest priority of the world HIV/AIDS agenda. The generation of a vaccine against HIV/AIDS has turned out to be extremely challenging, as indicated by > 20 years of unsuccessful attempts. This review discusses the major challenges in the field and key experimental evidence providing a rationale for the use of non-structural HIV proteins, such as Rev, Tat and Nef, either in the native form or expressed by viral vectors such as a replicating adeno-vector. These non-structural proteins alone or in combination with modified structural HIV-1 Env proteins represent a novel strategy for both preventative and therapeutic HIV/AIDS vaccine development.     

Targeting the human DEAD-box polypeptide 3 (DDX3) RNA helicase as a novel strategy to inhibit viral replication

Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high intrinsic mutation and replication rates of HIV-1 often lead to the emergence of drug resistant strains and consequent therapeutic failure. On this basis, cellular cofactors represent attractive new targets for HIV-1 chemotherapy, since targeting a cellular factor that is required for viral replication should help to overcome the problem of viral resistance. We and others have recently reported the identification of compounds suppressing HIV-1 replication by targeting the cellular DEAD-box helicase DDX3. These results provide a proof-of-principle for the feasibility of blocking HIV-1 infection by rendering the host cell environment less favorable for the virus. The rationale for such an approach and its implications in potentially overcoming the problem of drug resistance related to drugs targeting viral proteins will be discussed in the context of the known cellular functions of the DEAD-box helicase DDX3.     

Controlling HIV-1 Rev function

Although current therapies used in the treatment of HIV-1 infection have proven effective in reducing mortality due to the infection, the increase in drug resistant strains of the virus call for increased effort to explore and develop alternative treatment modalities. In this review, the various strategies to control HIV-1 replication through the disruption of Rev function are outlined. A wide range of methods have been developed including antisense DNA, ribozymes, decoy RNAs, transdominant proteins and suicide vectors targeted at disrupting Rev function. Although many of these methods have proven effective alone, it is hoped that a more robust antiviral response can be attained through combination of these strategies. As the methods of delivering these therapeutic agents matures through the development of lentiviral-based vectors, it is hoped that they will eventually reach the clinic where they may not only supplement the current treatment strategies but also provide resistance to those at high risk of infection or failing therapy.     

Novel inhibitors of human CMV

Human CMV (HCMV) is an opportunistic pathogen associated with significant morbidity and mortality among immunocompromised patients (in particular immunosuppressed patients with stem cell or solid organ transplantation, AIDS or cancer). Additionally, congenital HCMV infections are a leading cause of birth defects and infections in children, occurring in 1 to 2% of all live births. Drugs currently available for the treatment of HCMV diseases in the immunocompromised individual include ganciclovir, its oral prodrug valganciclovir, cidofovir, foscavir and fomivirsen. Although these drugs have proved successful in the management of HCMV disease in immunocompromised patients, their use is limited because of toxicity, poor oral bioavailability, modest efficacy and the development of drug resistance. Furthermore, no drug has been licensed for use in the treatment of congenital HCMV. Therefore, there is a need to develop new compounds against HCMV diseases. The search for novel inhibitors of HCMV replication has led to the identification of new molecular targets such as the viral protein kinase UL97, and the viral proteins involved in genome replication or in DNA maturation and egress. Moreover, a new strategy based on the identification of specific cellular targets required for viral replication has been developed. This review focuses on non-nucleoside compounds that inhibit specific viral processes and on cell-based approaches that result in the selective inhibition of virus replication.