Variable Fitness Impact of HIV-1 Escape Mutations to Cytotoxic T Lymphocyte (CTL) Response

Abstract

Human lymphocyte antigen (HLA)-restricted CD8+ cytotoxic T lymphocytes (CTL) target and kill HIV-infected cells expressing cognate viral epitopes. This response selects for escape mutations within CTL epitopes that can diminish viral replication fitness. Here, we assess the fitness impact of escape mutations emerging in seven CTL epitopes in the gp120 Env and p24 Gag coding regions of an individual followed longitudinally from the time of acute HIV-1 infection, as well as some of these same epitopes recognized in other HIV-1-infected individuals. Nine dominant mutations appeared in five gp120 epitopes within the first year of infection, whereas all four mutations found in two p24 epitopes emerged after nearly two years of infection. These mutations were introduced individually into the autologous gene found in acute infection and then placed into a full-length, infectious viral genome. When competed against virus expressing the parental protein, fitness loss was observed with only one of the nine gp120 mutations, whereas four had no effect and three conferred a slight increase in fitness. In contrast, mutations conferring CTL escape in the p24 epitopes significantly decreased viral fitness. One particular escape mutation within a p24 epitope was associated with reduced peptide recognition and high viral fitness costs but was replaced by a fitness-neutral mutation. This mutation appeared to alter epitope processing concomitant with a reduced CTL response. In conclusion, CTL escape mutations in HIV-1 Gag p24 were associated with significant fitness costs, whereas most escape mutations in the Env gene were fitness neutral, suggesting a balance between immunologic escape and replicative fitness costs.

Immune escape from HIV-specific antibody-dependent cellular cytotoxicity (ADCC) pressure

“…More potent ADCC antibodies are likely to target conserved or functional domains of viral proteins. The Env protein is highly diverse and readily escapes CTL and NAb responses with apparently minimal fitness costs (13,(20)(21)(22). It is possible that any fitness cost of ADCC escape in Env could be small.…”

Coordinate linkage of HIV evolution reveals regions of immunological vulnerability

“…Whereas one mutation in interface residues may still allow formation of p24 hexamers and assembly of the hexamers to form the viral capsid, multiple simultaneous mutations would likely destabilize these protein-protein interfaces. Fitness cost predictions of multiple mutations in sector 3, and comparisons with available data (20), are included in SI Appendix, Table S9-S11.…”

Vertical T cell immunodominance and epitope entropy determine HIV-1 escape

“…Evidence that T cell selected HIV-1 escape can confer fitness costs to the virus in vivo comes from the consistent reversion of escaped virus when transmitted into patients with different HLA types (33,34). Documented examples of reversion are limited to a few well-described epitopes, but in vitro studies of particular epitopes have repeatedly shown lower replication following introduction of HIV-1 T cell escape mutations into chimeric or full-length viruses (35)(36)(37)(38). Both types of study have focused on epitopes presented by protective HLA, with limited fitness cost information available on the vast majority of epitopes.…”