Viral fitness implications of variation within an immunodominant CD8+ T-cell epitope of HIV-1

• Published in: Virology (New York, N.Y.) Vol. 388; no. 1; pp. 137 - 146
• Main Authors: Christie, N.M, Willer, D.O, Lobritz, M.A, Chan, J.K, Arts, E.J, Ostrowski, M.A, Cochrane, A, Luscher, M.A, MacDonald, K.S
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.05.2009
• Subjects: Biological Evolution; CD8-Positive T-Lymphocytes - physiology; Cell Line; CTL escape; Gene Expression Regulation, Viral - physiology; Genetic Variation; HIV; HIV Antigens - genetics; HIV-1 - genetics; HIV-1 - immunology; Human immunodeficiency virus 1; Humans; Immune pressure; Immunodominant Epitopes - physiology; Infectious Disease; Viral fitness; HIV; CTL escape; Viral fitness; Immune pressure
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2009.03.003

Abstract Cytotoxic T-lymphocyte (CTL) epitopes within the HIV genome are subject to negative and positive selective pressures, the balance of which influences CTL escape at a given epitope. We investigated whether viral fitness requirements dictate conservation of the HLA-A2 restricted immunodominant epitope SLYNTVATL (SL9). Viral clones incorporating changes throughout the SL9 epitope region were compared to consensus SL9 virus in terms of replication kinetics and relative viral fitness. Constructs recapitulating in vivo SL9-CTL escape variants showed markedly little effect on replication and fitness, as did non-natural conservative mutations targeting immunologically relevant positions of the epitope. Although certain residues of the epitope were constrained by viral requirements, our research reveals that there are multiple SL9 variants that are well tolerated virologically but fail to arise in vivo . In light of this data, assumptions regarding the balance of immune and viral selective pressures on this immunodominant epitope sequence need to be reassessed.