By Howard E. Gendelman (University of Nebraska Medical Centre, USA) writing in Lentiviruses and Macrophages: Molecular and Cellular Interactions

For chronic lentiviral infections mononuclear phagocytes remain an enigma. On the one hand they are among the first cells contacted by virus and, despite a virtual armada of immunological tools, still serve as means to both spread and contain infection. Virus particles can simultaneously assemble and hide in intracellular compartments, largely free from immune attack. Interestingly, the mononuclear phagocytes are not destroyed by the virus and throughout infection they still contribute to host immunity while at the same time perpetuating lentiviral dissemination. Infected mononuclear phagocytes are readily observed in lymph nodes and organs such as the lung and brain, where they produce cytotoxic mediators that contribute to the development of disease.

For human immunodeficiency virus (HIV) infection functional impairment of infected mononuclear phagocytes likely accelerates immune deficiency. Thus, the questions most asked are how can a cell that possesses so many intrinsic defence mechanisms harbour such viral pathogens for prolonged time periods? How can mononuclear phagocytes serve both as sentries and vehicles for disseminating infection and inducing disease? Indeed, in regards to biology, for both ontogeny and phylogeny, mononuclear phagocytes are the most primitive sensors of tissue injury and as such serve to clear debris and simultaneously protect the host's homeostatic environment. Their roles serve the host in non-specific defence (innate immunity) and in initiating cell-specific protection (adaptive immunity).

A consistent evolutionary role resides in the ability of mononuclear phagocytes to engulf, digest and destroy cell and tissue debris through phagolysosomal fusion. Interestingly, mononuclear phagocytes can affect neighbouring lymphocytes and other immunocytes to perform similar functions, albeit by divergent mechanisms. Control of viral growth occurs together with the mononuclear phagocyte's notable possession of a vast repertoire of immune secretory factors that include pro-inflammatory cytokines, chemokines, arachidonic acid and its metabolites, platelet activating factor, nitric oxide, quinolinic acid, amongst others. These serve to regulate immune defence, cell mobility, antigen presentation, immune activation, and cell differentiation. During disease such secretions are induced by infection and affect inflammatory processes that speed cell and tissue injury leading to clinical symptoms and morbidities. This, in the case of common lentiviral tissue injuries, leads to substantive lung, brain, blood, and joint diseases.

Clearly, the role played by mononuclear phagocytes in the pathogenesis of lentiviral infections is seemingly complex and quite multifaceted. Viral spread from mononuclear phagocytes to mononuclear phagocytes and from mononuclear phagocytes to T cells and across cell and tissue barriers is equally vast and complicated. Historically, how this primary mover for innate immunity serves as a source for restricted and productive lentiviral replication seems almost illogical.

First, with an armada of microbial clearance activities that include phagocytosis, intracellular killing, secretion of bioactive antiviral factors such as interferons and biodegradable enzymes, it is of great interest that lentiviruses can enter these cells and replicate over prolonged time periods measured in months or even years. How virus evades innate immune responses, nevertheless, remains poorly understood, even following nearly 30 years of study.

Second is the feature of transcriptional control for viral persistence. A host of factors control the viral life cycle and are regulated through the mononuclear phagocytes external environment which allows virus to continue to replicate in the face of often robust humoral and cellular immune responses and more recently during potent antiretroviral therapies for HIV. In this scenario, virus buds into endocytic compartments with limited cell surface expression of viral proteins and in this context parallels the ancient Trojan horse mythology of being protected inside a sheath of secrecy. It was such a stratagem that Odysseus employed which allowed the Greeks to enter the city of Troy and end a conflict which had lasted 10 years. The Greeks built a huge wooden figure of a horse and left it as a parting gift for Athena as they pretended to sail away from Troy. The jubilant Trojans pulled the wheeled horse into the city unaware of the armed Greek soldiers hiding in the Trojan horse's belly. The Greek soldiers poured out of a trap door in the horse's belly and quickly killed the Trojans, setting fire to the city and thereby winning the war. For lentiviruses, it is analogous to their strategy of entering the brain and overcoming the restrictions imposed by a seemingly impermeable blood-brain barrier through the establishment of a chemokine gradient. Certainly, lentiviruses use mononuclear phagocytes as a ploy to enter the host and evade immune surveillance thereby escaping detection in a similar manner to the Greek soldiers in the Trojan Horse.

Third, there is a curious balance of host defence and dissemination of viral infection. Dendritic cells and tissue macrophages are readily infected in body fluids and are the likely cellular source of viral spread both from animal to animal or person to person through seminal and blood macrophages and/or monocytes and dendritic cells and carriage of virus throughout the body.

Fourth are the severe and lasting functional consequences of viral infection and immune activation as it occurs during disease. This is typified by secretion of inflammatory toxins manufactured and released by mononuclear phagocytes that cause tissue injuries commonly in the lung, the joints, and the central nervous system. The latter perhaps has received the most intense study in regards to relationships between mononuclear phagocytes function, neuroinflammation, and neurodegeneration. The field spawned biomarker discovery in proteomics and metabolomics and adjunctive therapeutic developments aimed at better understanding and combating disordered mononuclear phagocytes function during lentiviral disease.

Fifth, intra- and inter-cellular mononuclear phagocytes mechanisms govern the viral life cycle. How lentiviruses hijack subcellular organelles and the cytoskeletal machinery to complete their life cycle is a fascinating area for research activities. Added to such complexities are the relationships between innate and adaptive immunity including spread of virus. Even more importantly, perhaps, is how regulatory and effector T cells amongst other cells that come in contact with macrophages affect macrophage function in disease and either exacerbate or control the tempo of disease.

By Howard E. Gendelman (University of Nebraska Medical Centre, USA) writing in Lentiviruses and Macrophages: Molecular and Cellular Interactions

Labels: HIV infection, Howard E Gendelman, Human immunodeficiency virus, lentivirus, lentiviruses, Mononuclear phagocytes

The pioneering phase of the study of retroviruses resulted in the identification of viruses associated with diseases in chickens, mice and cats. Retroviruses have since been isolated from many vertebrate species, and classified into seven genera that can be grouped into two general categories.

Alpharetroviruses, betaretroviruses and gammaretroviruses are genetically simple, encoding only nucleoprotein, matrix, capsid, reverse transcriptase, integrase, protease and envelope proteins. Deltaretroviruses, epsilonretroviruses, lentiviruses and spumaviruses are considered complex because they encode in addition to the proteins listed above, a number of ancillary proteins that often play an important role in gene regulation.

Simple mammalian gammaretroviruses and the complex piscine epsilonretroviruses and bovine leukemia virus have shed light on the mechanisms of viral function, evolution and pathogenesis within the animal kingdom that hosts them.

Further reading: Retroviruses: Molecular Biology, Genomics and Pathogenesis

Labels: Alpharetroviruses, Betaretroviruses, Bovine leukemia virus, Deltaretroviruses, Epsilonretroviruses, Gammaretroviruses, lentiviruses, Spumaviruses

Gammaretroviral and lentiviral vectors for gene therapy have been developed that mediate stable genetic modification of treated cells by chromosomal integration of the transferred vector genomes. This is highly desired, not only for research use, but also for clinical gene therapy aiming at the long-term correction of genetic defects, e.g., in stem and progenitor cells.

Retroviral vector particles with tropism for various target cells have been designed. Due to split genome vector design the risk of replication-competent retrovirus formation has been minimized. Gammaretroviral and lentiviral vectors have so far been used in more than 300 clinical trials, addressing treatment options for various diseases. In some cases these trials resulted in benefit for treated patients suffering from life threatening disease.

Insertional mutagenesis due to vector integration in or next to cellular proto-oncogenes was concluded to be necessary for the lymphoproliferative disease observed in some patients treated with gammaretrovirally modified haematopoietic stem cells for X-linked severe combined immunodeficiency disease. These findings prompted the design of gammaretroviral vectors harbouring self-inactivating (SIN) Long Terminal Repeats (LTRs), which current lentiviral vectors already have.

SIN vectors may reduce the effect of insertional mutagenesis and proto-oncogene activation, thereby reducing the risk of oncogenesis. With a view to future clinical use, new developments such as cell entry targeting will further improve the safety and efficacy of retroviral vectors.

Further reading:
Retroviruses: Molecular Biology, Genomics and Pathogenesis
Lentiviruses and Macrophages: Molecular and Cellular Interactions

Labels: Lentiviral, lentivirus, lentiviruses, Retroviral vectors, Vectors for Gene Delivery

Retroviruses comprise a diverse family of enveloped RNA viruses, remarkable for their use of reverse transcription of viral RNA into linear double stranded DNA during replication and the subsequent integration of this DNA into the genome of the host cell. Members of this family include important pathogens such as HIV-1, feline leukemia, and several cancer-causing viruses.

Research into retroviruses led to the discovery of oncogenes, a major advance in the field of cancer genetics. Studies of retroviruses have contributed greatly to our understanding of mechanisms that regulate eukaryotic gene expression.

Retroviruses are proving to be valuable research tools in molecular biology and have been used successfully in gene therapy (e.g. to treat X-linked severe combined immunodeficiency).

Further reading: Retroviruses: Molecular Biology, Genomics and Pathogenesis

Labels: Lentiviral, lentivirus, lentiviruses, Retroviral, Retrovirus, retroviruses

Lentiviruses and Macrophages: Molecular and Cellular Interactions
Edited by: Moira Desport
Published: 2010 ISBN: 978-1-904455-60-8
In this timely book, top lentivirus and macrophage specialists comprehensively review cutting-edge topics in the molecular and cellular biology of the lentivirus-macrophage interaction. Topics include lentivirus tropism and disease, macrophage biology, macrophage in HIV-1 infection and disease progression, post-entry restrictions to lentiviral replication, HIV-2 tropism and disease, SHIV model of disease, the felid immunodeficiency viruses, EIAV, small ruminant lentiviruses, bovine lentiviruses, coinfections and superinfections.

Further reading: Lentiviruses and Macrophages: Molecular and Cellular Interactions

Labels: aids, books, dengue virus, hiv, lentivirus, lentiviruses, new book, virology books, virus books