Nonhuman primate models of intrauterine cytomegalovirus infection.

Congenital human cytomegalovirus (HCMV) infection has long been recognized as a threat to the developing fetus, even though studies have shown that only a subset of congenital infections results in clinical signs of disease. Among the estimated 8000 children who develop sequelae from congenital CMV infection each year in the United States alone, most suffer permanent developmental defects within the central nervous system. Because there is currently no approved vaccine for HCMV, and anti-HCMV drugs are not administered to gravid women with congenital infection because of potential toxicity to the fetus, there is a clear clinical need for effective strategies that minimize infection in the mother, transplacental transmission of the virus, and/or fetal disease.

Experimental coinfection of rhesus macaques with rhesus cytomegalovirus and simian immunodeficiency virus: pathogenesis.

Human cytomegalovirus (HCMV) possesses low pathogenic potential in an immunocompetent host. In the immunosuppressed host, however, a wide spectrum of infection outcomes, ranging from asymptomatic to life threatening, can follow either primary or nonprimary infection. The variability in the manifestations of HCMV infection in immunosuppressed individuals implies that there is a threshold of host antiviral immunity that can effectively limit disease potential.

Potent immunosuppressive activities of cytomegalovirus-encoded interleukin-10.

Cytomegalovirus (CMV) has highly evolved mechanisms for avoiding detection by the host immune system. Recently, in the genomes of human and primate CMV, a novel gene comprising segments of noncontiguous open reading frames was identified and found to have limited predicted homology to endogenous cellular interleukin-10 (IL-10). Here we investigate the biological activities of the CMV IL-10-like gene product and show it to possess potent immunosuppressive properties.

Immunogenicity of a DNA vaccine against herpes B virus in mice and rhesus macaques.

Herpes B virus (Cercopithecine herpesvirus 1) is endemic in captive macaque populations and poses a serious threat to humans who work with macaques or their tissues. A vaccine that could prevent or limit B virus infection in macaques would lessen occupational risk. To that end, a DNA vaccine plasmid expressing the B virus glycoprotein B (gB) was constructed and tested for immunogenicity in mice and macaques.

Construction and in vitro characterization of attenuated feline immunodeficiency virus long terminal repeat mutant viruses.

AP-1- and ATF-binding sites are cis-acting transcriptional elements within the U3 domain of the feline immunodeficiency virus (FIV) long terminal repeat (LTR) that serve as targets for cellular activation pathways and may regulate virus replication. We report that FIV LTR mutant proviruses encoding U3 deletions of the ATF-binding sequence exhibited restricted virus expression and replication in both feline lymphocytes and macrophages. In contrast, deletion of the AP-1 site had negligible effects on virus expression and replication.

Protective immunity against feline immunodeficiency virus induced by inoculation with vif-deleted proviral DNA.

To determine whether live-attenuated feline immunodeficiency virus (FIV) proviral DNA will induce protective immunity, a plasmid clone constructed with a FIV provirus containing a deletion in the viral accessory gene vif (FIV-pPPR-Deltavif) was inoculated as proviral DNA into four cats by the intramuscular route. After 43 weeks, these cats were boosted with the same proviral plasmid. Analysis of peripheral blood mononuclear cells at several time points after the primary and booster inoculations revealed no detectable virus or proviral DNA.

Primate cytomegaloviruses encode and express an IL-10-like protein.

An open reading frame (ORF) with homology to interleukin-10 (IL-10) has been identified in rhesus cytomegalovirus (RhCMV). The IL-10-like protein is generated from a multispliced, polyadenylated early gene transcript encompassing part of the corresponding UL111A ORF of human CMV (HCMV). Immunological analyses confirm expression of the IL-10-like protein both in tissue culture and in RhCMV-infected rhesus macaques.

Pathogenesis of experimental rhesus cytomegalovirus infection.

Human cytomegalovirus (HCMV) establishes and maintains a lifelong persistence following infection in an immunocompetent host. The determinants of a stable virus-host relationship are poorly defined. A nonhuman primate model for HCMV was used to investigate virological and host parameters of infection in a healthy host.

The feline immunodeficiency virus vif gene is required for productive infection of feline peripheral blood mononuclear cells and monocyte-derived macrophages.

The role of the feline immunodeficiency virus (FIV) vif gene in establishing productive infection in feline peripheral blood mononuclear cells (PBMCs) and monocyte-derived macrophages (MDMs) was examined in cell culture systems. A 375-bp deletion was introduced into the vif gene of the wild-type FIV-pPPR infectious molecular clone to produce Vif deletion mutant FIV-pPPRDeltavif. This mutant FIV proviral construct expressed FIV proteins p24gag and gp100env in transfected Crandell feline kidney cells as measured by immunoprecipitation and Western blot analysis as well as immunocytochemical analysis; these cultures produced very low levels of virus by cocultivation of transfected cells with PBMCs and K-258 cells, as measured by production of p24gag.