Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents - Volume 4, Issue 1, 2004

In this issue experts in the field highlight recent advances in our understanding of HIV, the AIDS virus. The current issue will give an overview also of how the rapidly evolving knowledge about HIV may lead the way to new therapies not only for HIV but also for other diseases such as cancer, genetic deficiencies, autoimmune diseases and fungal infections. Much progress has been made; however, a cure for HIV has not yet been found and seems to be a goal hard to reach. Till a cure for HIV is found, the major goal is, besides preventing new infections, to increase life expectancy and quality of individuals already infected with HIV. New and improved drug- and immune-based therapies with increased efficacy and fewer side effects may be part of this solution. Not all side effects of current anti-HIV drugs are harmful. This issue will also summarize how some of the side effects of these drugs may even open new avenues into the treatment of cancer, autoimmune diseases and fungal infections. I wish you an insightful reading and thank the contributors very much.

Clinical application of gene transfer technology continues to be investigated as a possible future therapeutic modality for a variety of human diseases. This article discusses the basic characteristics of human immunodeficiency virus type 1 (HIV-1) that have made it both an attractive target for possible gene therapy intervention and a potential tool for use in a variety of other clinical gene transfer applications. The molecular genetics and features of the replication cycle of HIV-1 relevant to gene therapy are discussed. Fundamental strategies for using gene transfer as an anti-HIV-1 therapy are reviewed, using examples of specific targets and methodology to illustrate each concept. The rationale for development and components of HIV-1 vector systems for use in the clinical gene therapy are discussed.

Similarly to other virus infections, entry of HIV into the host initiates immediate responses of the immune system. Elements of the innate immunity are activated to control HIV propagation until the induction of adaptive immunity. Innate immunity participates not only in the early phase of immune defence against HIV, but its effect can be observed continuously and concerns also modification of the adaptive immune response. In this review, we discuss the role of the innate immune system in early and late HIV pathogenesis and the escape mechanisms, which protect HIV from destruction by innate immune responses. In this regard, we will mainly focus on the interaction of HIV with various elements of innate immunity, among these the complement system, as a major humoral component. Furthermore, the involvement of cellular components of innate immunity like natural killer cells, macrophages and dendritic cells in HIV infection will be reviewed.

The present review reflects on current strategies for the development of a vaccine or immunotherapy against HIV, the AIDS virus. The phenomena of HIV-infected long-term nonprogressors, the natural host of SIV and HAART-treated, HIV-positive subjects with discordant virus load / CD4 T cell count are discussed. The latter phenomena seem not to hyperactivate the immune system and strategies to specifically suppress HIV-induced immune hyperactivation may help restore a functioning immune system and to further delay or eliminate the onset of AIDS.

Drug treatment of human immunodeficiency virus (HIV) infection is a rapidly changing field. Practice changes as new drugs become available, results of studies are published, and clinical experience is accumulated. Accordingly, any review is likely to be outdated from the moment it is submitted, even before publication. In addition, the limitations inherent to a single review article of this length preclude in depth treatment of many important topics, including antiviral resistance testing and therapeutic drug monitoring. Other areas are not even addressed, such as treatment of special populations (including infants, children and pregnant women), “alternative therapy”, and use of HIV chemotherapeutics for perinatal, parenteral, or sexual postexposure prophylaxis. Nonetheless, every effort has been made to provide both a historical perspective and the most up-to-date information available on currently approved antiretroviral drugs, promising drug candidates in development, the status of laboratory monitoring pertinent to treatment and current treatment strategies for the HIV-infected adult patient. This review should serve as a useful summary for those now entering the field or seeking an overview of the current status of the chemotherapy of HIV infection.

What is largely known is that HIV-protease inhibitors (HIV-PI) have substantially contributed to the reduction of morbidity and mortality presently enjoyed by AIDS patients under highly active antiretroviral therapy (HAART). What is much less known is that they share rather remarkable inhibitory properties against a large panel of pathogenic microorganisms for which aspartyl proteinases (AP) play a critical host-aggressive role. This review focuses on structural and enzymatic properties of aspartyl- and other proteinases in the search of a rationale to address and explain their rather wide and previously unsuspected antimicrobial properties. Special emphasis is here placed on secretory AP of Candida albicans that has been the first of AP category being demonstrated to be affected by HIV-PI. It gathers the multifaceted evidence suggesting that direct AP inhibition by HIV-PI contained in HAART regimens plays a role in the early and potent activity exerted by these inhibitors against mucosal candidiasis. Mostly on the basis of detailed structural and sequence homology consideration, the review also discusses the possibility that more specific and potent protease inhibitors could constitute a new class of antimicrobials targeting virulence rather than microbial growth and so expanding the spectrum of active therapeutics in an era of threatening antimicrobial drug resistance and shortage of new, efficacious antimicrobials.