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