Reduced viral replication capacity of human immunodeficiency virus type 1 subtype C caused by cytotoxic-T-lymphocyte escape mutations in HLA-B57 epitopes of capsid protein.
Cytotoxic-T-lymphocyte (CTL) escape mutations in human immunodeficiency viruses encode amino acid substitutions in positions that disrupt CTL targeting, thereby increasing virus survival and conferring a relative fitness benefit. However, it is now clear that CTL escape mutations can also confer a fitness cost, and there is increasing evidence to suggest that in some cases, e.g., escape from HLA-B*57/B*5801-restricted responses, the costs to the escape virus may affect the clinical course of infection. To quantify the magnitude of the costs of HLA-B*57/B*5801 escape, a highly sensitive dual-infection assay that uses synonymous nucleotide sequence tags to quantify viral relative replication capacity (RRC) was developed. We then asked whether such CTL escape mutations had an impact equivalent to that seen for a benchmark mutation, the M184V antiretroviral drug resistance mutation of reverse transcriptase (RRC(V184) = 0.86). To answer the question, the RRCs were quantified for escape mutations in three immunodominant HLA-B*57/B*5801 epitopes in capsid: A146P in IW9 (RRC(P146) = 0.91), A163G in KF11 (RRC(G163) = 0.89), and T242N in TW10 (RRC(N242) = 0.86). Individually, the impact of the escape mutations on RRC was comparable to that of M184V, while coexpression of the mutations resulted in substantial further reductions, with the maximum impact observed for the triple mutant (RRC(P146-G163-N242) = 0.62). By comparison to M184V, the magnitude of the reductions in RRC caused by the escape mutations, particularly when coexpressed, suggests that the costs of escape are sufficient to affect in vivo viral dynamics and may thus play a role in the protective effect associated with HLA-B*57/B*5801.
Boutwell
Christian L
CL
Department of Immunology and Infectious Diseases, Harvard School of Public Health AIDS Initiative, Harvard School of Public Health, 651 Huntington Avenue, Boston, Massachusetts 02115, USA.
Rowley
Christopher F
CF
Essex
M
M
D019943:Amino Acid Substitution / Q000276:immunology; D036022:Capsid Proteins / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D015235:HLA-B Antigens / Q000276:immunology*; D006801:Humans; D020125:Mutation, Missense; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014779:Virus Replication
D036022:Capsid Proteins; D000939:Epitopes; D015235:HLA-B Antigens; C103707:HLA-B57 antigen