Current Drug Targets - Infectious Disorders - Volume 3, Issue 2, 2003

Major Histocompatibility (MHC)-restricted Cytotoxic T-Lymphocytes (CTL) kill Human Immunodeficiency Virus (HIV)-infected cells. In addition, activated CD8+ T-lymphocytes from HIV-infected individuals suppress virus replication in vitro by producing antiviral factor (CAF). The effector mechanism(s) of CAF involves modulation of HIV gene transcription, is non-cytolytic and mediated in part by soluble antiviral factors. Initially, CAF activity was shown to be more vigorous in activated CD8+ cells and cell free supernatants (SNs) from asymptomatic individuals compared to those with AIDS, suggesting a protective role in vivo. CAF-mediated suppression is also evident in animal models of immunodeficiency virus infection. Several soluble molecules that contribute to non-cytolytic virus suppression have been characterised, including α- and β-chemokines and interleukin-16 (IL-16), but these are distinct from CAF. Two agents possessing certain CAF-like characteristics, modified antithrombin 111 (AT111) and the human a-defensins, have been described but their antiviral mechanisms are not fully understood. CAF-secretion may not be virus-specific as similar activity is found in activated CD8+ cells / SNs from humans and chimpanzees seronegative for HIV-1. Recent data indicates that the secretion of CAF is MHC-restricted and both cytolytic and non-cytolytic mechanisms are mediated by CTL. If the latter is correct, a single appropriate stimulus could be used to enhance both effector mechanisms in vivo. This paper reviews research aimed at characterising HIV-suppressive factors and raises other questions that must be considered for the development of prophylactic and therapeutic strategies leading to the safe and effective control of HIV.

Immunosuppression associated with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) markedly increases the risk for development of several cancers. Despite its dramatic decrease in frequency after the introduction of highly active antiretroviral therapy (HAART), Kaposi's sarcoma (KS) remains the most common neoplastic manifestation of AIDS. KS is a multicentric angioproliferative tumor, characterized microscopically by spindle cells. KS cells produce and respond to angiogenic factors such as basic fibroblast growth factor (bFGF) and vascular endothelial growth factor-A (VEGF-A). In addition to cellular growth factors, the trans-activator HIV protein Tat plays a major role in the pathogenesis of AIDSrelated KS by augmenting the angiogenic activities of bFGF and VEGF-A, and activating the VEGF receptor-2. Viral products from the recently described Kaposi's sarcoma-associated herpesvirus (KSHV) also exhibit potent angiogenic activities. KSHV is consistently associated with KS and two lymphoproliferative disorders, primary effusion lymphoma (PEL) and the plasma cell variant of multicentric Castleman's disease (MCD). Several viral genes may contribute to the phenotype of PEL and MCD: among them, a viral homologue of interleukin-6 (vIL-6) has attracted much attention due to its potential to stimulate B cell growth and accelerate angiogenesis via VEGF-A induction. In this review, we summarize current knowledge and hypothesis regarding the cellular and viral angiogenic factors involved in the pathogeneses of AIDS-related malignancies, and discuss novel therapeutic strategies based on targeting proangiogenic factors.

Kaposi's sarcoma-associated herpesvirus (KSHV / HHV-8) is present in all Kaposi's sarcoma tumor cells as well as in several lymphomas that are linked to this agent. Every tumor cell expresses the viral latent protein LANA, which is required for KSHV latent replication and proper segregation of the viral episome. In certain tumors, other latent KSHV proteins (LANA- 2 / vIRF3, v-cyclin, v-IL6) are expressed as well. Since all herpesviruses persist for life in infected individuals, only eradication of latent virus can cure infection. The KSHV latent genes serve as bona fide tumor markers, but do they also provide targets for anti-tumor and / or anti-viral drugs? To decide this question we review the known biochemical interactions between KSHV latent proteins and their viral and cellular partners. Recent epidemiological studies show that KSHV lytic replication precedes KSHV associated cancers. Gancilovir has been linked to KS tumor regression, which implicates the KSHV-encoded polymerase as a potential intervention point. Yet, KSHV specific transactivators might represent more specific targets, as they have no cellular homologs. In particular Rta / orf50 is necessary and sufficient for lytic replication and deserves serious consideration as a target for KSHV-specific antivirals.

The development of high-grade B-cell lymphoma in Acquired Immunodeficiency Syndrome (AIDS) patients is a relatively late manifestation induced by Human Immunodeficiency Virus-1 (HIV) infection and is considered to be an AIDS-defining condition. Multiple, ongoing molecular and cytogenetic aberrations appear necessary for the development of AIDS-related lymphoma. Studying a panel of human B-cell lines derived from patients with Burkitt's lymphoma (BL) and AIDS-associated Burkitt's lymphoma (AIDS-BL) we had described constitutive expression and secretion of large amounts of Interleukin-16 (IL-16), Macrophage Inflammatory Protein-1α (MIP-1α), Macrophage Inflammatory Protein-1β (MIP-1β), Interleukin-12 (IL-12), Interleukin- 10 (IL-10), and Interleukin-7 (IL-7). Some of these cytokines like IL-16, MIP-1β, MIP-1α and Regulated upon activation normal T expressed and secreted (RANTES) are shown to have inhibitory effect on HIV replication. Interestingly, we identified a novel transcription factor family, Macrophage Inflammatory Protein-1α Nuclear Protein (MNP), which is suggested as a potential target for anti-retroviral therapy based on the implication of its role and involvement as a key regulator of MIP-1α. It is apparent, that HIV induces the production of a cascade of cytokines and cytokine receptors. Some of these molecules serve to increase the infection and replication of HIV per se, and some others serve to induce a state of B-cell growth, activation, and differentiation. This review attempts to delineate the complex mechanisms of viral, B-cell, oncogene, cytokine / cytokine receptor and transcription factor interactions that are involved in AIDS associated lymphomagenesis. Unfolding the relationship between cytokines and the underlying mechanisms of the disease will not only help in understanding the pathophysiology but also will facilitate focusing on the development of new diagnostic and therapeutic strategies.

The use of live-attenuated viruses as vaccines has been successful for the control of viral infections. However, the development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge. HIV infects cells of the immune system and results in a severe immunodeficiency. In addition, the ability of the virus to adapt to immune pressure and the ability to reside in an integrated form in host cells present hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes from different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immunity, however, a live-attenuated vaccine for HIV is problematic. The possibility of a live-attenuated vaccine to revert to a pathogenic form or recombine with a wild-type or defective virus in an infected individual is a drawback to this approach. Therefore, these vaccines are currently only being tested in non-human primate models. Live-attenuated vaccines are effective in stimulating immunity, however challenged animals rarely clear viral infection and the degree of attenuation directly correlates with the protection of animals from disease. Another particle-based vaccine approach for HIV involves the use of virus-like particles (VLPs). VLPs mimic the viral particle without causing an immunodeficiency disease. HIV-like particles (HIV-LP) are defined as self-assembling, non-replicating, nonpathogenic, genomeless particles that are similar in size and conformation to intact virions. A variety of VLPs for both HIV and SIV are currently in preclinical and clinical trials. This review focuses on the current knowledge regarding the immunogenicity and safety of particle-based vaccine strategies for HIV-1.

The induction of a Th-1 polarized immune response is believed to be advantageous when designing immunologic approaches for HIV therapy. DNA vaccines represent one of the best immunologic strategies capable of inducing such a response. From conception to clinical application it is now possible to rationally design DNA vaccines based on reliable experimental data, thus a systemic approach to the development of new and the enhancement of existing vaccine immunogens is now possible. The addition of adjuvants may also increase immunogenicity and depending on the choice of adjuvant, polarize the immune response. Other important factors in the formulation of a successful vaccine are the selection of administration route, heterologous or homologous prime / boost schedules, and the feasibility of the eventual clinical application. This review will summarize recently developed preventive and therapeutic vaccines, and carefully evaluate the advantages and potential risks for Human Immunodeficiency Virus (HIV) infected patients. Finally, the concept of “autovaccination” will be defined as it represents the basis for the development of our innovative therapeutic antigen presenting cell targeted HIV vaccine. DermaVir is the first topical vaccine, in combination with antiretroviral therapy, to demonstrate immunological and clinical benefits in a relevant animal model (chronically infected rhesus macaques).

The introduction of potent drug combinations comprising reverse transcriptase and protease inhibitors has dramatically altered the natural history of HIV disease, at least in the short term. Unfortunately, poor penetrability into different anatomic compartments, toxicity and drug resistance, are some of the problems related to their prolonged use. HIV's ability to mutate and become resistant along with the ongoing viral replication during HAART, which may lead to the emergence of independently evolving viral strains in different anatomic compartments and establishment of latent viral reservoirs also remain critical for the success and failure of antiretroviral therapy. Current drug therapies do not eliminate these viral reservoirs, nor do they discourage their formation. New strategies are needed for flushing hidden pockets of HIV in vivo. This review will focus mainly on novel strategies in the pipeline, along with the recent developments in the field.