title: Replication, immunogenicity, and protective properties of live-attenuated simian immunodeficiency viruses expressing interleukin-4 or interferon-gamma.
abstract: Nef deletion mutants of SIV-expressing interleukin-4 (SIV-IL4) or interferon-gamma (SIV-IFN) were constructed to study the effect of interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) on viral load, immunogenicity, and protective properties. Four rhesus monkeys were infected with SIV-IL4 and four were infected with SIV-IFN. During the acute phase of infection, the cell-associated viral load, but not the plasma viral RNA load, was approximately 10-fold lower in SIV-IFN-infected macaques than in SIV-IL4-infected rhesus monkeys. The viral load declined to hardly detectable levels 4 months postinfection in all animals. SIV antibody titers and the affinity of these antibodies were higher in SIV-IL4-infected macaques than in SIV-IFN-infected animals, consistent with a stimulation of T helper cell type 2 immune responses by IL-4. At peak viremia, there was a trend to higher interleukin-12 and perforin mRNA levels of the lymph nodes in the SIV-IFN-infected macaques than in the SIV-IL4-infected monkeys. Deletion of the viral IFN gene, but not the viral IL-4 gene, after the development of antiviral immune responses suggests a repressive effect of IFN, but not IL-4, on virus spread in vivo. A trend to higher set point viral RNA levels in SIV-IL4-infected monkeys in comparison to monkeys infected with the parental nef deletion mutant and similar viral RNA levels during the acute phase of infection suggest that IL-4 expression leads to a slight reduction in the control of virus replication by host immune responses. However, SIV-IL4 and SIV-IFN induced protection against a homologous challenge virus. Subsequent challenge with an SIV-HIV-1 hybrid virus (SHIV) also revealed protection in the absence of neutralizing antibodies.
authors.affiliation: Deutsches Primatenzentrum, Göttingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.forename: Björn R
authors.initials: BR
authors.lastname: Gundlach
authors.forename: Ulf
authors.initials: U
authors.lastname: Dittmer
authors.forename: Peter
authors.initials: P
authors.lastname: ten Haaft
authors.forename: Jonathan
authors.initials: J
authors.lastname: Heeney
authors.forename: Weiping
authors.initials: W
authors.lastname: Zou
authors.forename: Dominique
authors.initials: D
authors.lastname: Emilie
authors.forename: Sieghart
authors.initials: S
authors.lastname: Sopper
authors.forename: Klaus
authors.initials: K
authors.lastname: Uberla
mesh_terms: D000818:Animals; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000235:genetics*; D015847:Interleukin-4 / Q000235:genetics*; D008253:Macaca mulatta; D012333:RNA, Messenger / Q000032:analysis; D018449:SAIDS Vaccines / Q000276:immunology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000517:prevention & control / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000502:physiology; D014611:Vaccination; D014613:Vaccines, Attenuated / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication
chemical_list: D012333:RNA, Messenger; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D015847:Interleukin-4; D007371:Interferon-gamma