Current Pharmaceutical Design - Volume 9, Issue 18, 2003

A considerable progress has been made in recent years in the field of drug development against HIV. However, the current cost of AIDS drugs is the main obstacle that prevents their use in developing countries, where 95% of HIVinfected patients reside. The average yearly price of AIDS therapy and related health care of affected patients in the USA runs as high as $22,000 - an amount that corresponds to the combined income of as many as one hundred individuals in developing countries. Even in the USA, patients without medical insurance cannot afford the costly therapy. From the beginning it was clear that the most feasible and economic means of finding a solution is to identify anti-HIV drugs among already available and preferably over-the-counter pharmaceuticals, which have historically been used for unrelated clinical purposes. This review summarizes the development and discovery of affordable and potentially promising AIDS drugs. The anti-HIV activity of drugs and immunomodulating substances such as warfarin, cimetidine, levamisole, acetaminophen, gramicidin, and V-1 immunitor are described and discussed in relation to their clinical application. These compounds may be used in a cocktail drug combination.

Seizure disorders may complicate HIV disease, either as a direct result of HIV or as a manifestation of a secondary opportunistic infection. Unless a reversible cause of seizure activity can be discerned, current treatment guidelines recommend the use of anticonvulsant drugs in these patients. The concurrent use of antiretrovirals and anticonvulsants is a poorly studied area. Controlled clinical trials examining drug-drug and drug-disease interactions in this area are scant, leaving clinicians a therapeutic dilemma in terms of drug selection. Most studies have been retrospective in nature. Generalized seizures appear to be most common and occur most frequently in patients with more severe disease as indicated by lower mean CD4 + cell counts. In short follow-up periods, seizures appear to recur relatively frequently. Treatment of seizures in this population is hindered by a lack of clear data and numerous reports of drug-drug and drug-disease interactions. In order to best provide evidence-based care, controlled clinical trials are needed to discern which anticonvulsants are best suited for use in this population. Trials should also examine appropriate dose adjustments that may be warranted when anticonvulsants and antiretrovirals agents are used concurrently. Unless an identifiable and reversible cause of seizures is identified in this patient population seizures should be treated with standard therapy and close follow-up and monitoring. Newer anticonvulsants (i.e., gabapentin, tiagabine) with fewer drug interactions may be better alternatives when compared to older anticonvulsant agents. Clinicians might avoid valproic acid given some conflicting reports regarding potential for increasing viral replication.

Phospholipid analogs are a new class of compounds with potent activity against HIV infection when used alone or conjugated with other therapeutic agents. When conjugated to the nucleoside analog AZT, the resulting phospholipid- AZT conjugate can double target the virus replication cycle by inhibiting the viral reverse transcriptase (by AZT) and inducing the production of defective virus particles that lack functional gp120 expression on the virus surface resulting in reduced capacity to bind to CD4+ cells and inhibition of infected cell-cell fusion (by phospholipid). Of great interest are data indicating that selected phospholipids are active against drug resistant variants, a current major problem in treating HIV / AIDS and controlling the epidemic occurring in various parts of the world. The purpose of this review is to provide current information on the design and synthesis of various types of phospholipids and phospholipid conjugates, in-vitro and in-vivo antiviral activity, tissue distribution, intracellular metabolism, and mechanism of action. The future development of this novel class of compounds offers an exciting approach for reducing the toxicity and enhancing the distribution of therapeutic drugs to the lymphatics and central nervous system and suppressing the emergence of drug resistant variants of HIV.

HIV-1 entry is an attractive target for anti-HIV-1 therapy. However, there are no entry inhibitors approved for the clinical treatment of HIV-1 infection. This is likely to be changed in the near future since promising HIV-1 entry inhibitors, such as T20 and some chemokine receptor antagonists, are in the pipeline to join the repertoire of anti-HIV-1 therapeutics. This review will focus on what might be potential targets on the key components of the viral entry machinery, gp120 and gp41. These two molecules are the viral proteins responsible for HIV-1 entry. Binding to CD4 induces a series of structural changes in gp120 and allows it to interact with chemokine receptors. The receptor binding eventually triggers conformational changes in gp41, which result in the formation of a fusion active molecule to attack the cell membrane. The structural and functional motifs that operate this delicate fusion machinery could become the Achilles' heel of the virus.

Over 80 different α-defensin or β-defensin peptides are expressed by the leukocytes and epithelial cells of birds and mammals. Although their broad spectrum antimicrobial properties makes them candidates for therapeutic development, technical limitations related to their size (typically 30-45 residues) and complex structure have impeded such development. The minidefensins covered in this review are antimicrobial peptides with 16-18 residues, approximately half the number found in α-defensins. The θ-defensins are evolutionarily related to α- and β-defensins, but other minidefensins probably arose independently. Like α- or β-defensins, minidefensin molecules have a net positive charge and a largely betα-sheet structure that is stabilized by intramolecular disulfide bonds. Whereas α-defensins are found only in mammals and θ-defensins only in nonhuman primates, the other minidefensins come from widely divergent species, including horseshoe crabs, spiders, and pigs. Several α-defensins and minidefensins are effective inhibitors of HIV-1 infection in vitro, and recent evidence implicates α-defensins in resistance to HIV-1 progression in vivo. This review compares defensins and minidefensins with respect to their activity against HIV-1. It pays special attention to retrocyclins - the ancestral θ-defensins of humans, and their extant counterparts in rhesus monkeys. In addition to describing critical elements of their structure and unusual mode of formation, we will venture some predictions about using θ-defensins as antiviral agents.

Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself causes in a high proportion of patients a metabolic syndrome, characterized by lipodystrophy / lipoatrophy, dyslipidemia and insulin resistance that may be associated with an increase in peripheral artery and coronary artery diseases. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. All HIV-infected patients who are either candidates to antiretroviral therapy or who are already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk with the available guidelines and the interactions between antiretrovirals and drugs commonly used to treat cardiovascular disease.