AEGiS-15IAC: Reversion of CTL escape mutant simian immunodeficiency virus (SIV) in vivo: Implications for HIV vaccine development.

15th International AIDS Conference

Bangkok, Thailand - July 11-16, 2004

Reversion of CTL escape mutant simian immunodeficiency virus (SIV) in vivo: Implications for HIV vaccine development.

Int Conf AIDS 2004 Jul 11-16; 15:(abstract no. MoOrA1049)

Friedrich TC, Dodds EJ, Yant LJ, Vojnov L, Rudersdorf R, Cullen C, Evans DT, Desrosiers RC, Mothe BR, Sidney J, Sette A, Kunstman K, Wolinsky S, Piatak M, Lifson J, Hughes AL, Wilson N, O'Connor DH, Watkins DI
Wisconsin National Primate Research Center, Madison, WI, United States

BACKGROUND: Engendering cytotoxic T-lymphocyte (CTL) responses will likely be an important goal of HIV vaccines. However, CTL select for viral variants that escape immune detection. Transmission and maintenance of escape variants in human populations could pose an obstacle to HIV vaccine development.

METHODS: We modeled human transmission of escape variant viruses by infecting MHC-defined macaques with SIV isolates bearing escape mutations in known CTL epitopes, and following viral evolution. We also compared the fitness of cloned escape mutant viruses to wild type SIVmac239 in vitro.

RESULTS: We observed that escape mutations in a heterogeneous SIV isolate were lost upon passage to new animals. We then infected macaques with a cloned SIV bearing escape mutations in three immunodominant CTL epitopes. Each mutant epitope sequence continued to evolve in vivo, often re-establishing the original, CTL-susceptible sequence. In vitro replication assays suggested that CTL escape mutations were associated with a cost to viral fitness.

CONCLUSIONS: We conclude that escape from CTL responses can exact a cost to viral fitness and in the absence of selective pressure upon transmission to new hosts, these original escape mutants will be lost. This suggests that some HIV CTL epitopes will be maintained in human populations.

Keywords: AEGIS, SIV, AIDS Vaccines, Acquired Immunodeficiency Syndrome, HIV, HIV Seropositivity, Simian Acquired Immunodeficiency Syndrome, T-Lymphocytes, Cytotoxic, Immunodominant Epitopes, HIV-1, HIV Infections, HIV Antigens, Virus Replication, Macaca, Epitopes, Human Development, Animal, Humans, In Vitro, immunology, virology

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MoOrA1049