Primate and feline lentiviruses in current intrinsic immunity research: the cat is back.

Retroviral restriction factor research is explaining long-standing lentiviral mysteries. Asking why a particular retrovirus cannot complete a critical part of its life cycle in cells of a particular species has been the starting point for numerous discoveries, including heretofore elusive functions of HIV-1 accessory genes. The potential for therapeutic application is substantial. Analyzing the feline immunodeficiency virus (FIV) life cycle has been instrumental and the source of some surprising observations in this field. FIV is restricted in cells of various primates by several restriction factors including APOBEC3 proteins and, uniquely, TRIM proteins from both Old and New World monkeys. In contrast, the feline genome does not encode functional TRIM5alpha or TRIMCyp proteins and HIV-1 is primarily blocked in feline cells by APOBEC3 proteins. These can be overcome by inserting FIV vif or even SIVmac vif into HIV-1. The domestic cat and its lentivirus are positioned to offer strategic research opportunities as the field moves forward.

Lessons from the cat: development of vaccines against lentiviruses.

Feline immunodeficiency virus (FIV) is a natural infection of domestic cats, which produces a disease with many similarities to human immunodeficiency virus (HIV) infection in man. The virus is an important cause of morbidity and mortality in pet cats worldwide. As such an effective vaccine is desirable both for its use in veterinary medicine and also as a model for the development of an HIV vaccine. A large number of candidate vaccines have been tested against feline immunodeficiency virus. These include inactivated virus and infected cell vaccines, DNA and viral vectored vaccines, subunit and peptide vaccines and vaccines using bacterial vectors. Ultimately, the development of inactivated virus and infected cell vaccines led to the release of the first licensed vaccine against FIV, in 2002. This review highlights some of the difficulties associated with the development of lentiviral vaccines and some of the lessons that have been learned in the FIV model that are of particular relevance to the development of HIV vaccines.

Feline lentiviruses demonstrate differences in receptor repertoire and envelope structural elements.

Feline immunodeficiency virus (FIV) causes fatal disease in domestic cats via T cell depletion-mediated immunodeficiency. Pumas and lions are hosts for apparently apathogenic lentiviruses (PLV, LLV) distinct from FIV. We compared receptor use among these viruses by: (1) evaluating target cell susceptibility; (2) measuring viral replication following exposure to specific and non-specific receptor antagonists; and (3) comparing Env sequence and structural motifs. Most isolates of LLV and PLV productively infected domestic feline T cells, but differed from domestic cat FIV by infecting cells independent of CXCR4, demonstrating equivalent or enhanced replication following heparin exposure, and demonstrating substantial divergence in amino acid sequence and secondary structure in Env receptor binding domains. PLV infection was, however, inhibited by CD134/OX40 antibody. Thus, although PLV and LLV infection interfere with FIV superinfection, we conclude that LLV and PLV utilize novel, more promiscuous mechanisms for cell entry than FIV, underlying divergent tropism and biological properties of these viruses.

Feline lentivirus infection in nondomestic felids.

Human immunodeficiency virus and feline immunodeficiency virus are both lentiviruses that cause immunosuppressive disease. Similarities between these diseases have promoted the study of feline immunodeficiency virus as a model for human immunodeficiency virus. Not only have lentiviruses been found in domestic cats but they have been found in nondomestic felids as well. Florida panthers, African lions, and other nondomestic felids have been found to have antibodies directed against lentiviruses and each nondomestic cat has antibodies to a virus that is specific for that species. The phylogenetic relationships of these lentiviruses have been studied and mapped using nucleic acid sequencing technology. Phylogenetic mapping has been an important step for future development of vaccines and antiviral therapy.