Viruses are small obligate intracellular parasites with either a RNA or DNA genome that are surrounded by a protective protein coat and transfer their genetic material to infected cells.
Lentivirus represents a genus of slow viruses with long incubation period (months, even years) and a propensity to induce a wide range of pathologies in different animal species. Due to their rather flexible genome and a potential of transducing many forms of nondividing cells, lentiviruses have become one of the most widely used vectors for gene transfer.
According to the recent classification of International Committee on Taxonomy of Viruses (ICTV), Lentivirus genus belongs to the family Retroviridae and currently comprises of nine species: seven animal lentiviruses and two human lentiviruses.
Animal lentiviruses are bovine immunodeficiency virus (BIV), caprine arthritis encephalitis virus (CAEV), equine infectious anemia virus (EIAV), feline immunodeficiency virus (FIV), puma lentivirus (PLV), simian immunodeficiency virus (SIV) and visna/maedi virus (VMV). Human species are well-known human immunodeficinecy virus 1 (HIV-1) and human immunodeficiency virus 2 (HIV-2).
Lentivirus history and characteristics
The first actual description of a disease caused by a lentiviral agent came from the observation of the equine infectious anemia in France in 1843. Later, a slowly progressive disorder in sheep was noted in Iceland during the 1950s caused by VMV, which represented a severe form of pneumo-encephalopathy. In the 1960s, American researchers determined the etiology of leukemia and lymphosarcoma of cattle – the causative factor was a retrovirus (BIV), morphologically similar to VMV.
Several lineages of closely related human and simian immunodeficiency viruses (HIV and SIV, respectively) are found in primates, which can both result in the acquired immunodeficiency syndrome (AIDS). Simian immunodeficiency viruses are branching into the five additional lineages which are named according their host; those are African green monkey, chimpanzee, sooty mangabey, syke and mandrill SIVs.
Primates naturally infected with these viruses usually remain healthy without the development of AIDS-like diseases, but their transmission to humans gave rise to two genetically different viruses (HIV-1 and HIV-2), still closely related to their ancestral species. Both of these viruses can cause AIDS in humans, albeit their viral kinetics and pandemic potential significantly differ.
However, although lentiviruses are responsible for one of the worst pandemic in the history of mankind, today they are being used extensively for gene therapy and the development of gene vaccines. Their usefulness is reflected by the fact that they are devoid of viral proteins and stably incorporate into the target cells.
Furthermore, lentiviral vectors (developed from aforementioned complex retroviruses) have properties that overcome limitations of simple retroviral vectors. These include higher stability of viral particles and a lower frequency of insertional mutagenesis. The fact that they can transduce highly differentiated cells such as dendritic cells is crucial for their use in immunotherapy.
In order to begin its life cycle, the infectious lentiviral particle (virion) must first enter the cell. That occurs either via endocytosis or by direct fusion with the cell membrane, after the virus binds to the specific receptor. For HIV-1, the receptor is the T-cell surface lymphocyte marker CD4, although the virus also needs chemocine coreceptors (CXCR4/CCR5).
Upon entering the cell, a lentiviral core is released and reverse transcription takes place. The genetic material of the core is transported to the nucleus, where it integrates into the host cell chromosome in a process called provirus integration. Transcription takes place from integrated provirus, resulting with the transport of either full-length RNA genomes, or the formation of messenger RNAs which encode the enzymatic and structural proteins (translation).
The structural proteins formed during translation package the full-length RNA genome while virions bud from the surface of the cell, thus releasing them into the surroundings. Inside them the viral protease will exert its activities on specific polyproteins, liberating the structural proteins and conferring infectivity to such newly formed virions; hence they acquire the ability to start the life cycle all over again.