The development of an effective vaccine against human immunodeficiency virus is considered to be the most practicable means of controlling the advancing global AIDS epidemic. Studies with the domestic cat have demonstrated that vaccinal immunity to infection can be induced against feline immunodeficiency virus (FIV); however, protection is largely restricted to laboratory strains of FIV and does not extend to primary strains of the virus. We compared the pathogenicity of two prototypic vaccine challenge strains of FIV derived from molecular clones; the laboratory strain PET F14 and the primary strain GL8 414 . PET F14 established a low viral load and had no effect on CD4؉ -or CD8 ؉ -lymphocyte subsets. In contrast, GL8 414 established a high viral load and induced a significant reduction in the ratio of CD4؉ to CD8 ؉ lymphocytes by 15 weeks postinfection, suggesting that PET F14 may be a low-virulence-challenge virus. However, during long-term monitoring of the PET F14 -infected cats, we observed the emergence of variant viruses in two of three cats. Concomitant with the appearance of the variant viruses, designated 627 W135 and 628 W135, we observed an expansion of CD8 ؉ -lymphocyte subpopulations expressing reduced CD8 ␤-chain, a phenotype consistent with activation. The variant viruses both carried mutations that reduced the net charge of the V3 loop (K409Q and K409E), giving rise to a reduced ability of the Env proteins to both induce fusion and to establish productive infection in CXCR4-expressing cells. Further, following subsequent challenge of naïve cats with the mutant viruses, the viruses established higher viral loads and induced more marked alterations in CD8؉ -lymphocyte subpopulations than did the parent F14 strain of virus, suggesting that the E409K mutation in the PET F14 strain contributes to the attenuation of the virus.

It has been shown that cats can be protected against infection with the prototypic Petaluma strain of feline immunodeficiency virus (FIV PET ) using vaccines based on either inactivated virus particles or replicationdefective proviral DNA. However, the utility of such vaccines in the field is uncertain, given the absence of consistent protection against antigenically distinct strains and the concern that the Petaluma strain may be an unrepresentative, attenuated isolate. Since reduction of viral pathogenicity and dissemination may be useful outcomes of vaccination, even in the absence of complete protection, we tested whether either of these vaccine strategies ameliorates the early course of infection following challenge with heterologous and more virulent isolates. We now report that an inactivated virus vaccine, which generates high levels of virus neutralizing antibodies, confers reduced virus loads following challenge with two heterologous isolates, FIV AM6 and FIV GL8 . This vaccine also prevented the marked early decline in CD4/CD8 ratio seen in FIV GL8 -infected cats. In contrast, DNA vaccines based on either FIV PET or FIV GL8 , which induce cell-mediated responses but no detectable antiviral antibodies, protected a fraction of cats against infection with FIV PET but had no measurable effect on virus load when the infecting virus was FIV GL8 . These results indicate that the more virulent FIV GL8 is intrinsically more resistant to vaccinal immunity than the FIV PET strain and that a broad spectrum of responses which includes virus neutralizing antibodies is a desirable goal for lentivirus vaccine development.

Monoclonal antibody vpgl5 detects a 24-kDa cell surface protein on feline cells permissive for infection with feline immunodeficiency virus (FIV). The antibody blocks infection of FIV-susceptible cells, and expression of the vpgl5 marker is decreased in FIV-infected cells in vitro. These results suggest that the antibody may recognize an FIV receptor distinct from CD4.

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Direct inoculation of genetic material in DNA form is a novel approach to vaccination that has proved efficacious for a number of viral agents. We are interested in the potential of this approach for the delivery of vaccines based on attenuated or replication-defective retroviruses. Toward this goal, we tested the effect of intramuscular inoculation of a plasmid containing the entire genome of feline immunodeficiency virus (FIV-Petaluma, F14 clone). DNA delivery was compared with intramuscular or intraperitoneal inoculation of virus reconstituted from the same molecular clone. The outcome was monitored by serological analysis and quantitative virus load determination over a 31-week period. DNA inoculation was found to be a reliable means of infection, although seroconversion and the rise in PBMC virus load were delayed relative to intramuscular or intraperitoneal inoculation of virus. At 31 weeks, similar levels of proviral DNA were detected in central lymphoid tissue of all infected animals. In conclusion, DNA inoculation of proviral DNA will be of use as a novel method of cell-free virus challenge and may have further potential for the delivery of lentiviral vaccines.