Infection with "escaped" virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques.
An understanding of the mechanism(s) by which some individuals spontaneously control human immunodeficiency virus (HIV)/simian immunodeficiency virus replication may aid vaccine design. Approximately 50% of Indian rhesus macaques that express the major histocompatibility complex (MHC) class I allele Mamu-B*08 become elite controllers after infection with simian immunodeficiency virus SIVmac239. Mamu-B*08 has a binding motif that is very similar to that of HLA-B27, a human MHC class I allele associated with the elite control of HIV, suggesting that SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+) animals may be a good model for the elite control of HIV. The association with MHC class I alleles implicates CD8+ T cells and/or natural killer cells in the control of viral replication. We therefore introduced point mutations into eight Mamu-B*08-restricted CD8+ T-cell epitopes to investigate the contribution of epitope-specific CD8+ T-cell responses to the development of the control of viral replication. Ten Mamu-B*08+ macaques were infected with this mutant virus, 8X-SIVmac239. We compared immune responses and viral loads of these animals to those of wild-type SIVmac239-infected Mamu-B*08+ macaques. The five most immunodominant Mamu-B*08-restricted CD8+ T-cell responses were barely detectable in 8X-SIVmac239-infected animals. By 48 weeks postinfection, 2 of 10 8X-SIVmac239-infected Mamu-B*08+ animals controlled viral replication to <20,000 viral RNA (vRNA) copy equivalents (eq)/ml plasma, while 10 of 15 wild-type-infected Mamu-B*08+ animals had viral loads of <20,000 vRNA copy eq/ml (P = 0.04). Our results suggest that these epitope-specific CD8+ T-cell responses may play a role in establishing the control of viral replication in Mamu-B*08+ macaques.
Valentine
Laura E
LE
Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
Loffredo
John T
JT
Bean
Alex T
AT
León
Enrique J
EJ
MacNair
Caitlin E
CE
Beal
Dominic R
DR
Piaskowski
Shari M
SM
Klimentidis
Yann C
YC
Lank
Simon M
SM
Wiseman
Roger W
RW
Weinfurter
Jason T
JT
May
Gemma E
GE
Rakasz
Eva G
EG
Wilson
Nancy A
NA
Friedrich
Thomas C
TC
O'Connor
David H
DH
Allison
David B
DB
Watkins
David I
DI
D000818:Animals; D002460:Cell Line; D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005805:Genes, MHC Class I / Q000276:immunology; D014644:Genetic Variation / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D016297:Mutagenesis, Site-Directed; D016097:Simian Acquired Immunodeficiency Syndrome / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000472:pathogenicity*; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics*
D017931:DNA Primers; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I