Replication, immunogenicity, and protective properties of live-attenuated simian immunodeficiency viruses expressing interleukin-4 or interferon-gamma.
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.
Stahl-Hennig
Christiane
C
Deutsches Primatenzentrum, Göttingen, Germany.
Gundlach
Björn R
BR
Dittmer
Ulf
U
ten Haaft
Peter
P
Heeney
Jonathan
J
Zou
Weiping
W
Emilie
Dominique
D
Sopper
Sieghart
S
Uberla
Klaus
K
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
D012333:RNA, Messenger; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D015847:Interleukin-4; D007371:Interferon-gamma