Current Pharmaceutical Design - Volume 10, Issue 32, 2004

Approximately 100 million individuals worldwide have been infected with the human immunodeficiency virus (HIV) and developed the disease known as acquired immunodeficiency syndrome (AIDS). The pace of research in this field has produced challenges for scientists and clinicians to keep informed of the vast array of new information, particularly the area of anti-HIV drug design and therapy. In this issue of Current Pharmaceutical Design, Pereira and Paridaen summarize the various approaches for anti-HIV drug development [1]. Imamichi [2] and Yusa and Harada [3] describe the mechanisms for resistance of HIV-1 to reverse transcriptase and protease inhibitors. Whereas, Chen et al. describe the connection between drug resistance and viral fitness [4]. Izzedine et al. [5] review the effect of antiretroviral drugs on the renal system and Provencher et al. [6] describe the effects that these drugs have on cellular proteins and the involvement in HIV resistance. Finally, Kelly et al. [7] describe a potential new class of HIV drugs, known as Virostatics.

Highly active antiretroviral therapy (HAART) has markedly decreased mortality and morbidity in the developed world. HAART consists of a combination of three or more of the following classes of antiretroviral (ARV) drug: reverse transcriptase inhibitors, protease inhibitors and a recently approved fusion inhibitor. However, HAART cannot completely eradicate HIV from the body, results in long-term toxicity and eventually leads to the emergence of drug-resistant HIV strains. These problems prompt the search for potent new drugs that are active against drug-resistant viral strains and that can safely be combined with other ARV drugs. The aim of this review was to give an overview of new compounds in preclinical or early clinical development that interact with various steps in the HIV life cycle: viruscell attachment; gp120-CD4 binding; gp120-coreceptor binding; viral fusion; viral assembly and disassembly; reverse transcription; nuclear import of the pre-integration complex; proviral integration; viral transcription; processing of viral transcripts and nuclear export; assembly of new virions; cellular factors involved in HIV replication.

Currently, 20 drugs have been approved for Human Immunodeficiency Virus type-1 (HIV-1) clinical therapy. These drugs inhibit HIV-1 reverse transcriptase, protease, or virus entry. Introduction of a combination therapy with reverse transcriptase inhibitors and protease inhibitors has resulted in a drastic decrease in HIV-1 related mortality. Although the combination therapy can suppress viral replication below detection levels in current available assays, low levels of on-going viral replication still persist in some patients. Long-term administration of the combination therapy may increase selective pressure against viruses, and subsequently induce emergence of multiple drug-resistant HIV-1 variants. Attempts have been made to design novel antiretroviral drugs that would be able to suppress replication of the resistant variants. At present, several investigational drugs are being tested in clinical trials. These drugs target not only the resistant variants, but also improvement in oral bioavilability or other viral proteins such as HIV-1 integrase, ribonuclease H, and HIV-1 entry (CD4 attachment inhibitors, chemokine receptors antagonists, and fusion inhibitors). Understanding mechanism(s) of action of the drugs and mechanisms of drug resistance is necessary for successful designs in the next generation of anti-HIV-1 drugs. In this review, the mechanisms of action of reverse transcriptase- and protease-inhibitors, and the mechanism of resistance to these inhibitors, are described.

Protease inhibitors are effective antiviral agents which can lead to a severe decrease in HIV RNA copies in plasma of naïve patients, however even successful suppression of the virus with antiretroviral agents including protease inhibitor(s) (PI(s)) generates PI-resistant HIV-1 after long term treatment. Occasionally HIV-1 acquires cross-resistance to other PIs with which the patients have not been treated. Cross-resistance to multiple PIs (multi-PI resistance) leads to a restricted salvage strategy; therefore multi-PI resistance is one of the serious obstacles to efficient antiretroviral chemotherapy. The most common PI-resistance mechanism in HIV-1 is the emergence and accumulation of multiple amino acid substitutions within the viral protease. As well, additional substitutions in protease cleavage sites or substitutions in the Gag protein at non-cleavage sites are involved in recovery of the reduced replication fitness of HIV-1 caused by these mutations in the viral protease. To address or predict the resistance mechanisms of PIs, resistant HIV-1 variants have been intensively studied in vitro. However, the profiles of the amino acid substitutions obtained in PI resistant variants are more diverse and complex than that found in vitro. More elaborate in vitro systems for further analysis of acquisition of PI resistance mechanisms are needed.

The evolution of antiretroviral drug resistance is a major problem in the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Drug therapy failure is associated with accumulation of drug resistance mutations and results in the development of drug resistance. Drugs targeted against reverse transcriptase (RT) as well as drug-resistant RT have been shown to increase HIV-1 mutation frequencies. Furthermore, combinations of drug and drug-resistant RT can increase virus mutation frequencies in a multiplicative manner. The evolution of drug resistance also alters virus fitness. The correlation of increased HIV-1 mutation rates with the evolution of antiretroviral drug resistance indicates that drug failure could increase the likelihood of further resistance evolving from subsequent drug regimens. These observations parallel studies from microbial systems that provide evidence for a correlation between drug resistance development and increased pathogen mutation rates. Although increased mutant frequencies may be detrimental to effective therapy, the lethal mutagenesis of the HIV-1 genome may provide a new means for antiretroviral therapy.

Background. Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon. Aim of the review. Since renal insufficiency is not uncommon among HIV-infected patients treated with antiretroviral drugs, guidelines on how to use these drugs in the pattern of an altered renal function are mandatory. This review provides such guidelines established on the basis of pharmacokinetic and clinical studies reported in the international literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and clinical and / or biological manifestations are reviewed to help monitor renal tolerance in patients receiving these drugs. Conclusion. Antiretroviral drugs' dosage in HIV-infected patients with altered renal function should be cautiously determined. Drug dosage should not be systematically reduced since dosage adjustment is not mandatory for all therapies (ie. protease inhibitors). Furthermore, when dose reduction is necessary, pharmacokinetic and clinical data from the literature allows to establish practical guidelines on how to use these drugs in such patients.

Despite the significant progresses made in antiretroviral therapy, current drugs still cannot cure or prevent HIV infection. And all drugs continue to select for drug-resistant HIV strains. Consequently, new antiretroviral drugs are constantly being developed. To ensure safety, these drugs are usually designed to inhibit viral proteins. But cellular proteins are also emerging as potential targets for new antiretroviral drugs. Two drugs that target cellular proteins inhibit HIV replication in vitro, hydroxyurea (HU) and pharmacological cyclin-dependent kinase inhibitors (PCIs). HU has been tested in clinical trials, commonly in combination therapies. PCIs, which are newer drugs, have just started to be tested in animal models of HIV-induced disease. Herein, we will review the HIV replication cycle and discuss the biological causes why strains resistant to antiviral drugs are so easily selected for. We will then discuss current antiretroviral drugs and HU before focusing on PCIs. PCIs have demonstrated to be effective against wild-type and drug-resistant strains of HIV in vitro, while selecting for no drug resistance. PCIs are additive with conventional antiviral drugs against herpes simplex virus, which suggests that they could also be additive with antiretroviral drugs. Since PCIs are proving surprisingly safe in human clinical trials (against cancer), they may be developed as clinical antiretroviral drugs in the near future. Recent and exciting studies indicate that PCIs ameliorate the pathogenesis of an animal model of HIV-induced nephropathy. We can expect that the full potential of PCIs as antiretroviral drugs will be explored in the coming years.

The combination of three or more antiretroviral drugs is referred to as highly active antiretroviral therapy (HAART) and constitutes the standard of care for HIV-1 patients in industrialized nations. Although HAART is usually effective in reducing viral load and re-constituting CD4 counts, latent virus reservoirs persist, and as many as 60 years therapy [1, 2] may be required to eradicate the virus. Meanwhile, patients are likely to experience drug related toxicity and may have to change therapy due to the emergence of drug resistant strains. For these reasons, the search for different therapeutic approaches continues. A new concept of antiviral / cytostatic (“virostatics”) drugs has been proposed within the context of HAART to restrict virus target populations (CD4+ T lymphocytes), target viral reservoirs, and possibly restore immune functions, by reducing excess immune activation, a fundamental component of HIV / AIDS pathogenesis. These virostatics include drugs such as hydroxyurea, mycophenolic acid, leflunomide and rapamycin, which are currently used for other therapeutic indications; and other experimental drugs, which are not for human use. They utilize multiple novel mechanisms of action to impede HIV by targeting host cellular proteins that are not susceptible to mutation. Therefore, their resistance profile appears to be quite favorable. Since many of these drugs act by inhibiting the synthesis of deoxynucleotides, essential for HIV reverse transcription, they favor the incorporation of nucleoside analogues into viral DNA, thus synergizing with the antiviral activity of currently used nucleoside reverse transcriptase inhibitors (NRTI). The rationale for the use of virostatics in HIV / AIDS, their mechanism of action, and ongoing preclinical and clinical research will be reviewed.

The DNA mismatch repair system maintains genomic stability by correcting DNA sequence errors generated during DNA replication, during genetic exchanges between chromosomes i.e., recombination, and by correcting DNA lesions caused by mutagenic agents such as cis-platinum. Post-synthesis mismatch repair improves almost 1000-fold the fidelity of DNA replication; however, the functions of mismatch repair proteins extend well beyond DNA repair. Recent studies suggest that mismatch repair is part of the machinery that couples DNA damage and repair to cell cycle regulation and apoptosis. These studies indicate that tolerance to certain DNA lesions (such as methylation and cis-platinum adducts) is associated with inefficient activation of cell cycle checkpoints and inefficient activation of apoptosis in mismatch repair deficient cells. Hence, mismatch repair proteins regulate the survival threshold to DNA damage, and this function provides a novel platform for understanding the role of mismatch repair in B cells, in tumor formation, as well as in resistance to chemotherapy. In this communication, we review how mismatch repair may contribute to the physiology of cells and may be regulated by the intracellular trafficking of mismatch repair proteins.

Current biological therapies for inflammatory bowel disease reflect the exponential advancement in understanding the human intestinal immune system and particularly the biology of intestinal inflammation over the past decade. The better understanding of the mechanisms of inflammatory bowel disease has evolved from descriptive clinical data and genetically engineered animal models. It led to great interest in a variety of new therapeutic agents and procedures with novel actions. This review will discuss the mechanisms of biologics (antibodies against pro-inflammatory cytokines, T-cell antibodies, anti-inflammatory cytokines, adhesion molecule blockers, growth factors, colony stimulating factors, fusion proteins, antisense oligonucleotides, hormones, immunostimulatory DNA (ISS-DNA, CpG Oligodeoxynucleotides) and parasites (Trichuris suis eggs), used in inflammatory bowel disease and summarize the available data on investigational and approved agents, and briefly touch on probiotics and extracorporeal immunomodulation (leukocyte apheresis and photoapheresis). Based on the data discussed, it appears that biologics may play an increasing role in managing inflammatory bowel disease in the near future.