Cat Transgenesis and Feline Versus Human AIDS

Abstract

A number of animal lentiviruses—such as the maedi-visna virus, the caprine arthritis-encephalitis virus, the equine infectious anemia virus, and the simian immunodeficiency virus— are known to share many biological features in common with the human immunodeficiency virus (HIV), the causative agent of acquired immunodeficiency syndrome (AIDS) in humans. Furthermore, infections caused by the aforementioned viruses have been regarded for a long time as valuable comparative models for the study of the pathology and pathogenesis of HIV infection. As highlighted in an intriguing article recently published in Nature Methods, this appears to be also true for feline immunodeficiency virus (FIV), the causative agent of feline AIDS, which makes the cat an ‘‘ideal’’ investigation model for human AIDS, despite the existence of some notable distinguishing features between FIV and HIV infection in terms of survival and progression to AIDS. Interestingly, over 2 decades before the first description of FIV in 1987, the feline leukemia virus—a well-known oncogenic retrovirus—had been discovered in cats affected by lymphosarcoma, with feline leukemia virus infection becoming recognized as an excellent animal model for the study of viral oncogenesis in humans. A really fascinating and promising result of the work cited above, which is of potential relevance also for other FIVsusceptible felids increasingly threatened by extinction, is that lymphocytes from TRIMCyp (an antiretroviral restriction factor)–transgenic cats resist FIV replication. In this respect, it would also be of concern to compare the resistance to FIV replication of T-helper 1 (Th1) versus Th2 lymphocytes in the transgenic animals under study. In fact, as far as HIV infection’s pathogenesis is still concerned, cumulative evidence exists that Th2-dominated immune responses favor a more rapid evolution toward full-blown AIDS, with a HIV-driven Th1 to Th2 adaptive immunity switch having been also suggested to occur. Furthermore, detailed in vitro studies on FIV-infected cat T lymphocytes have shown that interleukin-12 (IL-12), a cytokine playing an important role in Th1-dependent immune responses, significantly inhibits virus replication and cell apoptosis in a dose-dependent manner, with virtually no inhibitory effect on both FIV replication and apoptosis being exerted by IL-10, a cytokine having a relevant role in Th2-dominated immune responses. It would be of great value to assess whether there is variation in the resistance to FIV colonization and replication between the 2 aforementioned T-lymphocyte subsets (Th1 vs Th2 lymphocytes) in relation to the ‘‘predominant’’ T-cell immunophenotype of TRIMCyp-transgenic cats. Similar investigations should be strongly encouraged also in ‘‘wild-type’’ cats, to properly evaluate whether FIV infection displays a different pathogenetic behavior in Th1dominant versus Th2-dominant cats. This is closely related, among others, to the possibility that FIV infection may ultimately result in the selection, under natural conditions, of a virus-resistant lymphocyte population or subpopulation, as also emphasized in the aforementioned article. The concepts and ideas outlined above, albeit speculative in their nature, lie upon the common solid ground that is provided by the importance progressively gained, throughout time, by ‘‘host-specific’’ biologic determinants—such as the predominant T-cell-based immune response—in modulating individual interaction dynamics with microbial pathogens, along with the kinetics, evolution, and final outcome of the infectious processes caused by the same agents. Within this broad and intriguing context, the very important lessons taught by HIV and by the natural history and biology of HIV infection among people appear to be of crucial relevance. And, with this being firmly kept in mind, there are few doubts that obtaining additional knowledge on the pathogenetic behavior of FIV infection in cats may shed further light on the complex interaction dynamics underlying the mutual relationship between HIV and humans.