Universität zu Köln

Schommers, P., Martrus, G., Matschl, U., Sirignano, M., Luetgehetmann, M., Richert, L., Hope, T. J., Faetkenheuer, G. and Altfeld, M. (2016). Changes in HIV-1 Capsid Stability Induced by Common Cytotoxic-T-Lymphocyte-Driven Viral Sequence Mutations. J. Virol., 90 (16). S. 7579 - 7587. WASHINGTON: AMER SOC MICROBIOLOGY. ISSN 1098-5514

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Abstract

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. IMPORTANCE 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schommers, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martrus, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Matschl, U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sirignano, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Luetgehetmann, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richert, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hope, T. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Faetkenheuer, G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altfeld, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-268051
DOI:	10.1128/JVI.00867-16
Journal or Publication Title:	J. Virol.
Volume:	90
Number:	16
Page Range:	S. 7579 - 7587
Date:	2016
Publisher:	AMER SOC MICROBIOLOGY
Place of Publication:	WASHINGTON
ISSN:	1098-5514
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IMMUNODEFICIENCY-VIRUS TYPE-1; INNATE IMMUNE RECOGNITION; REVERSE TRANSCRIPTION; ESCAPE MUTATIONS; DENDRITIC CELLS; CYCLOSPORINE-A; INFECTED-CELLS; P24 GAG; RESTRICTION; REPLICATION Multiple languages Virology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26805