MicrobiologyBytes

The main impediment to a cure for HIV is the existence of long-lasting treatment resistant virus reservoirs. This review discusses what is currently known about reservoirs, including their formation and maintenance, while focusing on latently infected CD4+ T cells. It compares several different in vivo and in vitro models of latency and comments on how each model may reflect the properties of reservoirs in vivo, especially with regard to cell phenotype, since recent studies demonstrate that multiple CD4+ T cell subsets contribute to HIV reservoirs and that with HAART and disease progression the relative contribution of different subsets may change. It also focuses on the direct infection of resting CD4+ T cells as a source of reservoir formation and as a model of latency, since recent results help explain the misconception that resting CD4+ T cells appeared to be resistant to HIV in vitro.

HIV reservoirs and latency models. Virology. 2011 411(2): 344-354

Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy.

Clinical Management of HIV Drug Resistance. Viruses 2011, 3(4), 347-378; doi:10.3390/v3040347

“We live in an era in which we depend on antibiotics, and other antimicrobial medicines to treat conditions that decades ago, or even a few years ago in the case of HIV/AIDS, would have proved fatal. When antimicrobial resistance – also known as drug resistance – occurs, it renders these medicines ineffective. For World Health Day 2011, WHO will be calling for intensified global commitment to safeguard these medicines for future generations. Antimicrobial resistance – the theme of World Health Day 2011, 7 April 2011 – and its global spread, threatens the continued effectiveness of many medicines used today to treat infectious diseases. For World Health Day 2011, WHO will call on governments and stakeholders to implement the policies and practices needed to prevent and counter the emergence of highly resistant microorganisms.”

via WHO | World Health Day – 7 April 2011

Background
When to initiate antiretroviral therapy in HIV infected patients is a difficult clinical decision. Actually, it is still a matter of discussion whether early highly active antiretroviral therapy (HAART) during primary HIV infection may influence the dynamics of the viral rebound, in case of therapy interruption, and overall the main disease course.
Methods
In this article we use a computational model and clinical data to identify the role of HAART timing on the residual capability to control HIV rebound after treatment suspension. Analyses of clinical data from three groups of patients initiating HAART respectively before seroconversion (very early), during the acute phase (early) and in the chronic phase (late), evidence differences arising from the very early events of the viral infection.
Results
The computational model allows a fine grain assessment of the impact of HAART timing on the disease outcome, from acute to chronic HIV-1 infection. Both patients’ data and computer simulations reveal that HAART timing may indeed affect the HIV control capability after treatment discontinuation. In particular, we find a median time to viral rebound that is significantly longer in very early than in late patients.
Conclusions
A timing threshold is identified, corresponding to approximately three weeks post-infection, after which the capability to control HIV replication is lost. Conversely, HAART initiation occurring within three weeks from the infection could allow to preserve a significant control capability. This time could be related to the global triggering of uncontrolled immune activation, affecting residual immune competence preservation and HIV reservoir establishment.

Timely HAART initiation may pave the way for a better viral control. BMC Infectious Diseases 2011, 11: 56 doi:10.1186/1471-2334-11-56

Cidofovir is an acyclic nucleoside analog approved since 1996 for clinical use in the treatment of cytomegalovirus (CMV) retinitis in AIDS patients. Cidofovir (CDV) has broad-spectrum activity against DNA viruses, including herpes-, adeno-, polyoma-, papilloma- and poxviruses. Among poxviruses, cidofovir has shown in vitro activity against orthopox [vaccinia, variola (smallpox), cowpox, monkeypox, camelpox, ectromelia], molluscipox [molluscum contagiosum] and parapox [orf] viruses. The anti-poxvirus activity of cidofovir in vivo has been shown in different models of infection when the compound was administered either intraperitoneal, intranasal (aerosolized) or topically. In humans, cidofovir has been successfully used for the treatment of recalcitrant molluscum contagiosum virus and orf virus in immunocompromised patients. CDV remains a reference compound against poxviruses and holds potential for the therapy and short-term prophylaxis of not only orthopox- but also parapox- and molluscipoxvirus infections.

Cidofovir Activity against Poxvirus Infections. (2010) Viruses 2(12): 2803-2830 doi:10.3390/v2122803

Related:

• Molluscum contagiosum
• Poxvirus DNA factories
• Lipid Membranes in Poxvirus Replication

Human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the most prevalent deadly chronic viral diseases. HIV is treated by small molecule inhibitors. HBV is treated by immunomodulation and small molecule inhibitors. HCV is currently treated primarily by immunomodulation but many small molecules are in clinical development. Although HIV is a retrovirus, HBV is a double-stranded DNA virus, and HCV is a single-stranded RNA virus, antiviral drug resistance complicates the development of drugs and the successful treatment of each of these viruses. Although their replication cycles, therapeutic targets, and evolutionary mechanisms are different, the fundamental approaches to identifying and characterizing HIV, HBV, and HCV drug resistance are similar. This review describes the evolution of HIV, HBV, and HCV within individuals and populations and the genetic mechanisms associated with drug resistance to each of the antiviral drug classes used for their treatment.

Comparison of the Mechanisms of Drug Resistance among HIV, Hepatitis B, and Hepatitis C. Viruses. 2010; 2(12):2696-2739. doi:10.3390/v2122696

Related:

• Update on HBV and HCV Therapy
• Can HIV infection be eradicated through use of potent antiviral agents?
• Plugging the holes in hepatitis C virus antiviral therapy

Dengue virus infection is a growing public health problem with up to 100 million cases annually, and neither vaccines nor effective therapies are available. To search for the ways of preventing and treating dengue infections we need to better understand their molecular mechanisms. As with many other viruses, dengue virus enters cells by fusion between the viral membrane and the membrane of intracellular vesicles (endosomes). In this paper the authors explore the fusion stage of dengue virus entry in different experimental systems ranging from virus fusion to artificial lipid membranes to fusion inside the cells. While earlier work on dengue virus entry has focused on the virus protein that mediates fusion, they found that effective action of this protein requires specific lipid composition of the membrane the virus fuses to. In effect, this lipid dependence allows virus to control intracellular location of the fusion event and, thus, the place of its RNA release by exploiting cell-controlled differences between lipid compositions of different organelles the virus travels through. The essential role of the interactions between dengue virus and its lipid cofactors during virus entry suggests that these interactions may be targeted in drug design.

Dengue Virus Ensures Its Fusion in Late Endosomes Using Compartment-Specific Lipids. PLoS Pathog 6(10): e1001131. doi:10.1371/journal.ppat.1001131
Many enveloped viruses invade cells via endocytosis and use different environmental factors as triggers for virus-endosome fusion that delivers viral genome into cytosol. Intriguingly, dengue virus (DEN), the most prevalent mosquito-borne virus that infects up to 100 million people each year, fuses only in late endosomes, while activation of DEN protein fusogen glycoprotein E is triggered already at pH characteristic for early endosomes. Are there any cofactors that time DEN fusion to virion entry into late endosomes? Here we show that DEN utilizes bis(monoacylglycero)phosphate, a lipid specific to late endosomes, as a co-factor for its endosomal acidification-dependent fusion machinery. Effective virus fusion to plasma- and intracellular- membranes, as well as to protein-free liposomes, requires the target membrane to contain anionic lipids such as bis(monoacylglycero)phosphate and phosphatidylserine. Anionic lipids act downstream of low-pH-dependent fusion stages and promote the advance from the earliest hemifusion intermediates to the fusion pore opening. To reach anionic lipid-enriched late endosomes, DEN travels through acidified early endosomes, but we found that low pH-dependent loss of fusogenic properties of DEN is relatively slow in the presence of anionic lipid-free target membranes. We propose that anionic lipid-dependence of DEN fusion machinery protects it against premature irreversible restructuring and inactivation and ensures viral fusion in late endosomes, where the virus encounters anionic lipids for the first time during entry. Currently there are neither vaccines nor effective therapies for DEN, and the essential role of the newly identified DEN-bis(monoacylglycero)phosphate interactions in viral genome escape from the endosome suggests a novel target for drug design.

Related:

• Dengue Virus
• Pathogenesis and treatment of dengue fever

No.

How do I know? Because the scientists who did the research say so:

The idea that these powerful techniques with undoubted side effects would ever be applied to something as trivial as the common cold is laughable. If only BBC News had kept its head and gone with a sensible headline such as “Is science on the verge of curing Lassa fever?”.

And what happended to the BBC News policy of linking to the original research article?

Marine natural products are a continued focus for drug discovery and have provided many important therapeutic agents. Lead compounds with biomedical potential have been isolated from marine invertebrates, bacteria, and fungi. Each year numerous compounds with an array of biological activities are reported, but to-date only 13 molecules have entered into the clinical pipeline. Four molecules have been approved for clinical use, one of which is approved only in the EU. The approved molecules include two nucleosides based on sponge-derived nucleosides, a cone snail peptide, and a metabolite isolated from a tunicate. Marine microbes have received growing attention as the sources for bioactive metabolites and have great potential to increase the number of marine natural products in clinical trials. The sustainable and economic supply of the active pharmaceutical ingredient is often easier to achieve for compounds produced through microbial fermentation approaches versus the cultivation of slower growing macroorganisms.

Marine natural products provide an excellent opportunity to study diverse and unique compounds not readily accessible from any other source leading to expansion of the pharmaceutical pipeline. Marine microbes can produce unique compounds covering new chemical space, and the utility of marine natural products is expanding beyond its original role in identification of new prototype drug leads into fields of study involving sustainable supplies of unique molecules using biosynthesis in conjunction with synthesis. Perhaps the greatest impact marine natural products has played is in revealing that unexplored and previously inaccessible chemical space can contribute to growth in the pharmaceutical pipeline. Improved methodologies in fermentation technologies, biosynthesis, and synthesis provide opportunities to both create and supply drug leads that would not be available by any single method independently. As a result pharmaceutical biotechnology in the future is certain to provide increasingly sophisticated molecular architecture assembled using biosynthesis and synthesis in concert.

The expanding role of marine microbes in pharmaceutical development. Curr Opin Biotechnol. Oct 16 2010
Marine microbes have received growing attention as sources of bioactive metabolites and offer a unique opportunity to both increase the number of marine natural products in clinical trials as well as expedite their development. This review focuses specifically on those molecules currently in the clinical pipeline that are established or highly likely to be produced by bacteria based on expanding circumstantial evidence. We also include an example of how compounds from harmful algal blooms may yield both tools for measuring environmental change as well as leads for pharmaceutical development. An example of the karlotoxin class of compounds isolated from the dinoflagellate Karlodinium veneficum reveals a significant environmental impact in the form of massive fish kills, but also provides opportunities to construct new molecules for the control of cancer and serum cholesterol assisted by tools associated with rational drug design.

Related:

• Biofilms Use Chemical Weapons
• New Approach for the Discovery of Antibiotics
• Predator and Prey