Construction, replication, and immunogenic properties of a simian immunodeficiency virus expressing interleukin-2.
To study the effect of interleukin-2 (IL-2) on simian immunodeficiency virus (SIV) replication, pathogenesis, and immunogenicity, we replaced the nef gene of SIVmac239 by the IL-2 coding region. The virus, designated SIV-IL2, stably expressed high levels of IL-2 in cell culture. In comparison to SIVmac239, SIV-IL2 replicated more efficiently in peripheral blood mononuclear cells in the absence of exogenously added IL-2. To determine whether this growth advantage would be of relevance in vivo, four juvenile rhesus monkeys were infected with SIV-IL2 and four monkeys were infected with a nef deletion mutant of SIV (SIVdeltaNU). After a peak in the cell-associated viral load 2 weeks postinfection, the viruses could barely be isolated 3 to 7 months postinfection. Mean capsid antigen levels were higher in the SIV-IL2 group than in the nef deletion group 2 weeks postinfection. Viruses reisolated from the SIV-IL2-infected animals expressed high levels of IL-2 during the acute phase of infection. Deletions in the IL-2 coding region of SIV-IL2 were observed in two of the SIV-IL2-infected macaques 3 months postinfection. Urinary neopterin levels, a marker for unspecific immune stimulation, were higher in the SIV-IL2-infected macaques than in SIVdeltaNU-infected animals during the acute phase of infection. The SIV-specific T-cell-proliferative response and antibody titers were similar in both groups. Cytotoxic T cells directed against viral antigens were detected in all SIV-IL2-infected macaques and in two of the SIVdeltaNU-infected animals. Expression of IL-2 did not seem to alter the attenuated phenotype of nef deletion mutants fundamentally, although there might have been a slight increase in virus replication and immune stimulation during the acute phase of infection. Deletion of the viral IL-2 gene 3 months postinfection could be a consequence of a selective disadvantage due to local coexpression of viral antigen and IL-2 in the presence of an antiviral immune response.
Gundlach
B R
BR
Institut fur Klinische und Molekulare Virologie, Universitat Erlangen-Nurnberg, Erlangen, Germany.
Linhart
H
H
Dittmer
U
U
Sopper
S
S
Reiprich
S
S
Fuchs
D
D
Fleckenstein
B
B
Hunsmann
G
G
Stahl-Hennig
C
C
Uberla
K
K
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004279:DNA, Viral; D017353:Gene Deletion; D015693:Gene Products, nef / Q000235:genetics / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000276:immunology* / Q000302:isolation & purification / Q000502:physiology; D014779:Virus Replication
D004279:DNA, Viral; D015693:Gene Products, nef; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins