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Session 7 Oral Abstracts
Immune Responses to HIV
Monday, 10 am - 12:30 pm
Presentation Time: 10:45 am
Room 2005


13
Selection, Transmission, and Reversion of an Antigen Processing CTL Escape Mutation in HIV-1
T M Allen*1, M Altfeld1, X G Yu1, K M O'Sullivan1, M Lichterfeld1, P K Lee1, S Le Gall1, B R Mothe2, D E Cohen3, K A Freedberg1, A Sette4, E S Rosenberg1, P J R Goulder5, C Brander1, and B D Walker1
1Partners AIDS Res. Ctr., Massachusetts Gen. Hosp., Harvard Med. Sch., Boston, USA; 2Epimmune, San Diego, CA, USA; 3Fenway Community Hlth. Ctr., Boston, MA, USA; 4La Jolla Inst. of Allergy and Immunology, San Diego, CA, USA; and 5Nuffield Dept. of Med., Pathogen Res., Oxford, UK

Background:  Viral escape mutations within defined CD8+ T-cell epitopes have been observed, providing strong evidence that viral evolution is influenced by CD8-mediated immune selection pressure. However, whether specific CD8+ T-cell responses play a similar role in the selection of mutations within regions flanking CTL epitopes--which may influence epitope presentation and recognition--remains unknown. Similarly, the effect that transmission and reversion of such escape mutations has on the development of host CD8+ T-cell responses remains poorly defined.

Methods:  Longitudinal analysis of HIV-1 Gag-specific CD8+ T-cell responses using an IFN-g ELISpot assay and Clade-B consensus peptides was performed on 21 subjects enrolled in the Boston Acute Infection Cohort. Population and clonal sequencing were performed using nested PCR and a set of Clade-B-specific PCR primers.

Results:  We observed development of a single amino acid mutation in persons bearing the frequently expressed HLA-A3 allele that simultaneously abrogated two dominant CD8+ T-cell responses in HIV-1 p17. This mutation was located within one targeted epitope and in the C-terminal flanking region of the second epitope. Intracytoplasmic expression of the variant HIV-1 p17 protein prevented recognition of both epitopes by T-cell clones, supporting a role for this mutation in impacting the antigen processing of one or both epitopes. HLA-A3 subjects acutely infected with strains possessing similar mutations did not initiate either response, illustrating a direct effect upon recognition through transmission of these mutations. In vivo reversion of a transmitted CD8 escape mutation in one subject allowed for delayed induction of both HLA-A3-restricted CD8 responses.

Conclusions:  These data reveal an additional mechanism for HIV-1 to evade host immune responses and the effect of transmission of CD8 escape mutations on mounting of acute-phase responses. Reversion of a transmitted CD8 escape mutation suggests that some frequently occurring CD8 epitopes are not destined to be lost within the population, and implies a potential fitness cost to the virus from the mutation. A better understanding of these selective forces will be important for design of intracellularly processed HIV-1 vaccines.

Keywords: HIV-1; CD8 escape; antigen processing