By Dr Tomislav Meštrović, MD, PhD
Lentivirus genus represents a diverse, yet exceptionally cohesive group of retroviruses. Their influence on the health and general well-being of animals and humans alike has been enormous. Members of this group are found in primates, ungulates (cattle, sheep, horse and goat) and felids (cat). Vectors derived from these viruses that integrate into cellular DNA are promising tools for targeted gene therapy.
Common features of the genus
Although there are some clear distinctions between different viruses of the Lentivirus genus, they share a number of characteristic features overall. Those include infection of cells of the myeloid lineage (monocytes and macrophages), viral persistence regardless of host immune responses, protracted incubation periods and a variable, progressively degenerative disease course.
Lentiviruses can be separated into two basic groups: those that cause immunodeficinency disorder (HIV-1, HIV-2, SIV, FIV and potentially BIV) and those that do not (EIAV, JDV, SRLV). The host immune system is severely affected during the acute phase of progressive immunodeficiency lentiviral infections, and CD4 T-cell depletion is a hallmark of such infections.
Lentiviruses exploit a latent state in order to disseminate freely throughout the body and to avoid elimination from the immune system of the host. Inclination for establishing cellular latency varies greatly among primate species, and the phenomenon can be defined as the presence of proviral DNA (either integrated or episomal) in the absence of detectable viral RNA transcripts.
HIV-1 has been shown to persist in reservoirs that contain small pools of latently infected resting memory CD4 T-cells which carry integrated viral genome without the expression of viral proteins (unless the cells are stimulated to proliferate). On the other hand, macrophages do not divide and are incapable of establishing resting state – akin to CD4 T-cells.
All lentivirus disease progression has periods of clinical latency, but the fashion in which individual viruses interact with the infected host in order to accomplish it differs. Comparison of the disease processes observed in different lentiviruses emphasizes the complex interplay between replication, host immunity and ensuing latency.
Cellular tropism and pathogenesis
As mentioned before, all lentiviruses seem to share a superb ability to target cells of the myeloid lineage. These cells are non-dividing cells, which means that the viral genome must navigate through the intact nuclear membrane in order to access the cellular genome. Among retroviruses, lentiviruses have evolved the most efficacious machinery to achieve this goal – a trait that is extremely valuable in gene therapy.
Infections of monocytes and macrophages are thought to be pivotal for viral persistence and dissemination in various tissues. Those cells even represent the predominant type in different bodily fluids; for example, in semen the number of macrophages exceeds those of lymphocytes by more than 20-fold.
The infected cells frequently go undetected by the host immune system since they do not present viral antigens due to the lack of active replication. Therefore upon seeding in organ tissues, differentiation of latent monocytes activates viral replication and establishes reservoir sites in spite of the host immune response.
The main advantage of using lentiviruses as potent vectors for gene transfer is their propensity to transduce quiescent cells. Transduction of dendritic cells with such vectors results in their phenotypic and functional maturation. Whereas this represents an advantage when treating cancer or infections, it has the opposing effect when immunological tolerance is the desired consequence, as it is in the case of treatment of autoimmune disorders.
Last Updated: Dec 8, 2014