Changes in HIV-1 Capsid Stability Induced by Common Cytotoxic-T-Lymphocyte-Driven Viral Sequence Mutations.
HIV-1-infected individuals with protective HLA class I alleles exhibit better control of viremia and slower disease progression. Virus control in these individuals has been associated with strong and potent HIV-1-specific cytotoxic-T-lymphocyte (CTL) responses restricted by protective HLA alleles, but control of viremia also occurs in the presence of selected CTL escape mutations. CTL escape mutations restricted by protective HLA class I molecules are frequently located in the conserved p24 Gag sequence of HIV-1 that encodes the conical capsid core and have been suggested to reduce viral replication capacity. In this study, the consequences of well-described CTL-associated p24 Gag sequence mutations for HIV-1 capsid stability were assessed using a cyclosporine (CsA) washout assay. The frequently occurring HLA-B57- and HLA-B27-associated CTL escape mutations T242N and R264K resulted in delayed capsid uncoating, suggesting modulation of capsid stability. The described compensatory mutations L268M and S173A observed in R264K viruses reconstituted the capsid-uncoating half-time. Interestingly, capsid stability was correlated with infectivity. Taken together, these data demonstrate that CTL-driven escape mutations within p24 Gag restricted by protective HLA class I alleles have a significant impact on capsid stability that might contribute to the persistent control of viral replication observed despite viral escape from CTL responses.



Sequence mutations within p24 Gag selected by CTL responses restricted by protective HLA class I alleles have been associated with reduced viral fitness. However, the precise mechanisms underlying the reduced viral replication capacity and lower viral loads associated with these mutations remain unclear. Here, we demonstrate that dominant HLA-B27-associated CTL escape mutations within HIV-1 capsid lead to enhanced capsid rigidity, providing a possible mechanism for the reduced viral fitness of these variants.
Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.|Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.|German Center for Infection Research (DZIF), Cologne, Germany.
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P
Schommers
Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
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G
Martrus
Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
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U
Matschl
Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
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M
Sirignano
Department of Microbiology, Virology and Hygiene, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
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M
Lütgehetmann
Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.|INSERM U1219, INRIA SISTM, Bordeaux University, Bordeaux, France.
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L
Richert
Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
T J
TJ
Hope
Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany.|German Center for Infection Research (DZIF), Cologne, Germany.
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G
Fätkenheuer
Department of Virus Immunology, Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany marcus.altfeld@hpi.uni-hamburg.de.|Ragon Institute of MGH, MIT, and Harvard, Cambridge, Massachusetts, USA.
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Altfeld
D002213:Capsid / Q000737:chemistry / Q000276:immunology* / Q000502:physiology; D055598:Chemical Phenomena; D016655:HIV Core Protein p24 / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000737:chemistry / Q000235:genetics / Q000276:immunology* / Q000502:physiology; D020125:Mutation, Missense; D012641:Selection, Genetic; D013489:Suppression, Genetic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D057646:Virus Uncoating
D016655:HIV Core Protein p24