Current HIV Research - Volume 8, Issue 1, 2010

According to the UNAIDS 2008 global fact sheet an estimated 33 million people were living with HIV in 2007. This same year saw approximately 2.7 million new HIV infections as well as 2 million AIDS-related deaths. For over twenty years, regardless of our growing understanding of the many characteristics of HIV, ultimate control of the virus and its disease still eludes us. Since its original classification in the early 1980s we have been struggling to defeat this diminutive giant. This original classification of HIV as a lentivirus and the causative agent of AIDS was due to its morphological and serological resemblance to the ungulate lentiviruses that were more broadly known at the time. In fact, historically, the ungulate lentiviruses have been under investigation longer than any other virus group as the first viral etiology ascribed to an animal disease was an animal (ungulate) lentivirus. Animal, or more specifically non-primate, lentiviruses as a group are found endemically worldwide and infect a broad array of species. The lentivirus group was originally categorized as a distinguished subset of the family Retroviridae in the mid-1900s from classifications of maedi-visna viruses which, unlike the typical viruses characterized at that time, required months and years to manifest disease (lenti, from Latin, meaning slow). The diseases associated with animal lentiviral infections range from benign and subclinical to severely debilitating and lethal. During the past two decades since the discovery of HIV, research on the animal lentiviruses has increased markedly in an attempt to model the viral replication dynamics and disease processes associated with HIV-1/AIDS. In this issue of Current HIV Research these notable groups of non-primate animal lentiviruses are reviewed: beginning with the small ruminant lentiviruses (SRLV, previously referred to either as maedi-visna and/or caprine arthritis viruses), equine infectious anemia virus (EIAV), feline and bovine immunodeficiency viruses (FIV and BIV, respectively) and ending with the most recently identified lentivirus, Jembrana disease virus (JDV). The first two reviews cover the SRLV members of the lentivirus family. Leroux, Minardi, and Mornex introduce the SRLV with discussions of the reclassification of the lentivirus group with an emphasis on mechanisms leading to disease. In the second SRLV review, Blacklaws and Harkiss provide a comprehensive comparison between this mucosal pathogen and its cousin HIV highlighting the similarities of restricted replication and virus latency. Three reviews cover another of the ungulate lentiviruses, EIAV. Payne and Fuller discuss identification of viral pathogenesis determinants and how this work can be utilized to evaluate virus-host interactions. The second review by Carpenter and Dobbs describes using EIAV to evaluate the specific contributions of accessory proteins, particularly Rev, to in vivo viral variation and how studies such as these can be used to develop treatments for the prevention of lentiviral infections. Craigo and Montelaro overview studies in this equine lentivirus animal model of viral pathogenesis and vaccine development surveying the effects of envelope protein variation on both viral persistence and vaccine efficacy. Two reviews assess the feline member of the lentiviruses, FIV. Elder and colleagues highlight both the strengths and shortcomings of the FIV/cat model, particularly in regards to the development of antiviral drugs. The second FIV review by Yamamato and associates discuss the only commercially available lentiviral vaccine, Fel-O-Vax, its T-cell-related efficacy, and how these studies are being used to define the prophylactic epitopes needed for an HIV-1 vaccine for humans. The last two reviews cover the bovine lentiviruses, BIV and JDV. Corredor, St-Louis, and Archambault assess the biological and molecular aspects of BIV highlighting the regulatory/accessory viral genes involved in virus expression. In the last review, Desport and Lewis overview the current research on JDV covering the dynamics of viral replication, tropism and disease, molecular analysis of the viral genome and mRNA transcripts, and the current status of vaccine development and diagnostic assays. This issue gives a broad overview of the history and current state of research on the animal lentiviruses. As co-editors of this issue of Current HIV Research, we are very grateful for the time and effort that all of the authors committed to each review article. Furthermore, we hope that the reader will be stimulated by this collection of insightful review articles.

The bovine immunodeficiency virus (BIV) was isolated in 1969 from a cow, R-29, with a wasting syndrome suggesting bovine leucosis. The virus, first designated bovine visna-like virus, remained unstudied until HIV was discovered in 1983. Then, it was demonstrated in 1987 that the bovine R-29 isolate was a lentivirus with striking similarity to the human immunodeficieny virus (HIV). Moreover, BIV has the most complex genomic structure among all identified lentiviruses shown by several regulatory/accessory genes encoding proteins, some of which are involved in the regulation of virus gene expression. This manuscript aims to review biological and molecular aspects of BIV, with emphasis on regulatory/accessory viral genes/proteins which are involved in virus expression.

Feline immunodeficiency virus (FIV) discovered in 1986 is a lentivirus that causes AIDS in domestic cats. FIV is classified into five subtypes (A-E), and all subtypes and circulating intersubtype recombinants have been identified throughout the world. A commercial FIV vaccine, consisting of inactivated subtype-A and -D viruses (Fel-O-Vax FIV, Fort Dodge Animal Health), was released in the United States in 2002. The United States Department of Agriculture approved the commercial release of Fel-O-Vax FIV based on two efficacy trials using 105 laboratory cats and a major safety trial performed on 689 pet cats. The prototype and commercial FIV vaccines had broad prophylactic efficacy against global FIV subtypes and circulating intersubtype recombinants. The mechanisms of cross-subtype efficacy are attributed to FIV-specific T-cell immunity. Findings from these studies are being used to define the prophylactic epitopes needed for an HIV-1 vaccine for humans.

Small ruminant lentiviruses (SRLV) and human immunodeficiency viruses (HIV) are related retroviruses that cause multisystem disease usually over a long period of time. The viruses show similarities and differences in biological and pathogenic features. The basic retroviral genomic organization is complicated by the presence of a variable number of accessory genes in both viruses, though the structure is more complex in HIV. Both are mucosal pathogens, and infect cells of the monocyte-macrophage lineage. The main difference in cell tropism is that, unlike HIV, SRLV do not infect lymphocytes. A major feature of both pathogens is restricted replication and virus latency, which are partly responsible for the establishment of chronic infection usually lasting for life. The pathologies observed are similar in the early stages of both infections, and possibly following highly active anti-retroviral therapy (HAART). While the pathogenesis of HIVinduced disease during symptomatic stages is mainly due to secondary infections and neoplastic conditions, the early and post-HAART stages are associated with chronic inflammatory changes that resemble those found in SRLV diseases which are thought to be mediated by anti-virus immune responses.

Jembrana disease virus (JDV) is the most recently discovered member of the lentivirus family and causes an acute clinical disease in Bali cattle with a fatality rate of approximately 15%. It is genetically related to bovine immunodeficiency virus (BIV) to the extent that infections cannot yet be differentially diagnosed using serological assays due to cross-reacting epitopes. Despite their close genetic relationship the pathogenesis of JDV infection in Bali cattle is very different to that of BIV in cattle and is unusual for a member of this virus family. The dynamics of JDV replication and clearance during the acute stage of Jembrana disease, the viral tropism, molecular analysis of the viral genome and mRNA transcripts, and the current status of vaccine development and diagnostic assays are all reviewed to provide a greater understanding of the factors that make JDV such an unusual lentivirus.

Equine infectious anemia virus (EIAV) is a macrophage-tropic lentivirus that rapidly induces disease in experimentally infected horses. Because EIAV infection and replication is centered on the monocyte/macrophage and has a pronounced acute disease stage, it is a useful model system for understanding the contribution of monocyte/macrophages to other lentivirus-induced diseases. Genetic mapping studies utilizing chimeric proviruses in which parental viruses are acutely virulent or avirulent have allowed the identification of important regions that influence acute virulence. U3 regions in the viral LTR, surface envelope (SU) protein and the accessory S2 gene strongly influence acute disease expression. While the chimeric proviruses provide insight into genes or genome regions that affect viral pathogenesis, it is then necessary to further dissect those regions to focus on specific virus-host mechanisms that lead to disease expression. The V6 region of the viral env protein is an example of one identified region that may interact with the ELR-1 receptor in an important way and we are currently identifying S2 protein motifs required for disease expression.

FIV is a significant pathogen in the cat and is, in addition, the smallest available natural model for the study of lentivirus infections. Although divergent at the amino acid level, the cat lentivirus has an abundance of structural and pathophysiological commonalities with HIV and thus serves well as a model for development of intervention strategies relevant to infection in both cats and man. The following review highlights both the strengths and shortcomings of the FIV/cat model, particular as regards development of antiviral drugs.

Equine infectious anemia virus (EIAV) and its associated disease have presented a considerable challenge to veterinary medicine worldwide ever since its identification in the 19th century. Furthermore EIAV, along with its fellow animal lentiviruses, has been utilized as an animal model of HIV-1/AIDS research since the latters identification in the late 20th century. Like all lentiviruses, EIAV has been shown to have a high propensity for genomic sequence and antigenic variation, principally in its envelope (Env) proteins. However, unlike other lentiviruses, EIAV possesses a unique and dynamic disease presentation that enables consummate analyses of the interactions between a virus, host immune system, and the effects of viral evolution on vaccine efficacy. Hence, EIAV provides a novel animal lentivirus system with which to dissect the viral and immune correlates of vaccine efficacy and a system with which to examine vaccine candidates for the ability to elicit broadly protective vaccine immunity. The current review summarizes the key findings that have thus far provided a fundamental understanding of the role of the viral Env in immune control of infection, disease, and vaccine efficacy.

Equine infectious anemia virus (EIAV) is one of the most divergent members of the lentivirus subfamily of retroviruses and is considered a useful comparative model for molecular studies of lentivirus replication. The Rev protein of EIAV is functionally homologous with other lentiviral Revs and facilitates export of incompletely spliced viral mRNAs through a Crm1-dependent pathway. The trans- and cis-acting elements that mediate EIAV Rev function are similar to, but distinct from, the well-characterized elements in human immunodeficiency virus (HIV-1), the prototypical Rev protein. In addition, the EIAV rev sequence is highly variable in vivo, and changes in Rev phenotype correlate with changes in clinical stages of EIAV infection. This review summarizes the molecular biology of EIAV Rev-RRE interactions and the consequences of Rev variation in vivo. A comparative perspective of Rev activity may enhance understanding of an essential lentiviral protein and stimulate new strategies for treatment and prevention of lentivirus infections in vivo.

Lentiviruses from distinct animal species have in common their genomic organization, the induction of slowly progressive diseases over months or years, the large spectrum of induced symptoms and concerned organs, the frequent inapparent infection without any detectable clinical signs, their ability to persist into their hosts despite an often strong and mature immune response. Lentiviruses are also characterized by their genomic plasticity and the rapid evolution of the viral species. SRLVs infecting goats and sheep follow a genomic evolution pattern similar to that observed in HIV or in other lentiviruses. Based on limited number of complete sequences, they have been initially described as two distinct genetic groups evolving independently in sheep or goats, the ovine strains being closely related to each other and distinct from the caprine ones. Over the last 2 decades, the description of many partial or complete sequences of caprine and ovine field isolates from various geographical regions and their phylogenetic studies clearly evidenced the existence of a genetic continuum with viruses that did not simply cluster according to the animal species they were isolated from. Three classifications have been successively proposed and allowed to refine the SRLV phylogeny over time. Phylogenetic reconstructions support the existence of SRLV cross-species transmission in domestic and wild small ruminants.