Macaque long-term nonprogressors resist superinfection with multiple CD8+ T cell escape variants of simian immunodeficiency virus.
Human immunodeficiency virus (HIV)-positive individuals can be superinfected with different virus strains. Individuals who control an initial HIV infection are therefore still at risk for subsequent infection with divergent viruses, but the barriers to such superinfection remain unclear. Here we tested long-term nonprogressors' (LTNPs') susceptibility to superinfection using Indian rhesus macaques that express the major histocompatibility complex class I (MHC-I) allele Mamu-B 17, which is associated with control of the pathogenic AIDS virus SIVmac239. The Mamu-B 17-restricted CD8(+) T cell repertoire is focused almost entirely on 5 epitopes. We engineered a series of SIVmac239 variants bearing mutations in 3, 4, or all 5 of these epitopes and used them to serially challenge 2 Mamu-B 17-positive LTNPs. None of the escape variants caused breakthrough replication in LTNPs, although they readily infected Mamu-B 17-negative naive macaques. In vitro competing coculture assays and examination of viral evolution in hosts lacking Mamu-B 17 suggested that the mutant viruses had negligible defects in replicative fitness. Both LTNPs maintained robust immune responses, including simian immunodeficiency virus (SIV)-specific CD8(+) and CD4(+) T cells and neutralizing antibodies. Our results suggest that escape mutations in epitopes bound by "protective" MHC-I molecules may not be sufficient to establish superinfection in LTNPs.
Department of Pathobiological Sciences, University of Wisconsin School of Veterinary Medicine, Madison, Wisconsin 53706, USA.
Jason T
JT
Weinfurter
Gemma E
GE
May
Taeko
T
Soma
Ann J
AJ
Hessell
Enrique J
EJ
León
Caitlin E
CE
Macnair
Shari M
SM
Piaskowski
Kim
K
Weisgrau
Jessica
J
Furlott
Nicholas J
NJ
Maness
Jason
J
Reed
Nancy A
NA
Wilson
Eva G
EG
Rakasz
Dennis R
DR
Burton
Thomas C
TC
Friedrich
D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics*; D020276:HIV Long-Term Survivors; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism; D008253:Macaca mulatta / Q000276:immunology* / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000145:classification / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D015163:Superinfection / Q000276:immunology* / Q000821:virology
D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I