Conservation of Nef function across highly diverse lineages of SIVsmm.
BACKGROUND
SIVsmm is a simian immunodeficiency virus that persists efficiently without causing disease in naturally infected sooty mangabeys (SMs) but induces AIDS upon cross-species transmission to humans and macaques. Current phylogenetic data indicate that SIVsmm strains comprise a highly diverse group of viruses that can be subdivided into different lineages. Since only certain SIVsmm strains have successfully crossed the species barrier to humans and macaques, the question has been raised whether there are lineage specific differences in SIVsmm biology. In the present study we examined whether representatives of five different SIVsmm lineages show differences in the function of the accessory Nef protein, which plays an important role in viral persistence, transmission and pathogenesis.


RESULTS
We found that nef alleles from all SIVsmm lineages down-modulated CD4, MHC-I, CD28 and CD3 and up-regulated the invariant chain (Ii) associated with immature MHC-II molecules in human-derived cells. Moreover, they generally suppressed the responsiveness of virally infected T cells to activation, enhanced virion infectivity and promoted virus replication in human peripheral blood mononuclear cells. The functional activity of these nef alleles in the various assays varied substantially between different strains of SIVsmm but quantitative analyses did not reveal any significant lineage-specific differences in Nef function.


CONCLUSIONS
Nef alleles from different lineages of SIVsmm do not require adaptive changes to be functionally active in human cells. Strain rather than lineage-specific differences in Nef function may impact the virological and immunological feature of SIVsmm in SMs and possibly affected viral fitness and pathogenicity in human and macaque hosts.
Institute of Virology, University of Ulm, 89081 Ulm, Germany. jan.schmoekel@uniklinik-ulm.de
Jan
J
Schmökel
Hui
H
Li
Elizabeth
E
Bailes
Michael
M
Schindler
Guido
G
Silvestri
Beatrice H
BH
Hahn
Cristian
C
Apetrei
Frank
F
Kirchhoff
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D015498:HIV-2 / Q000737:chemistry / Q000235:genetics; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D010802:Phylogeny; D016415:Sequence Alignment; D015302:Simian Immunodeficiency Virus / Q000145:classification* / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D054334:Viral Regulatory and Accessory Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics
C429284:NEF protein, SIV; D054334:Viral Regulatory and Accessory Proteins; D054311:nef Gene Products, Human Immunodeficiency Virus