Hydrogen Bonding at a Conserved Threonine in Lentivirus Capsid Is Required for Virus Replication

The evolution of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) as they replicate in infected individuals reflects a balance between the pressure on the virus to mutate away from recognition by dominant epitope-specific cytotoxic T lymphocytes (CTL) and the structural constraints on the virus' ability to mutate. To gain a further understanding of the strategies employed by these viruses to maintain replication competency in the face of the intense selection pressure exerted by CTL, we have examined the replication fitness and morphological ramifications of a dominant epitope mutation and associated flanking amino acid substitutions on the capsid protein (CA) of SIV/simian-human immunodeficiency virus (SHIV). We show that a residue 2 mutation in the immunodominant p11C, C-M epitope (T47I) of SIV/SHIV not only decreased CA protein expression and viral replication, but it also blocked CA assembly in vitro and virion core condensation in vivo. However, these defects were restored by the introduction of upstream I26V and/or downstream I71V substitutions in CA. These findings demonstrate how flanking compensatory amino acid substitutions can facilitate viral escape from a dominant epitope-specific CTL response through the effects of these associated mutations on the structural integrity of SIV/SHIV.

Section: Vol 80 2006 Ctl Epitope Mutation Disrupts Viral Core Assemsupporting

confidence: 83%

mentioning

confidence: 99%

Compensatory Substitutions Restore Normal Core Assembly in Simian Immunodeficiency Virus Isolates with Gag Epitope Cytotoxic T-Lymphocyte Escape Mutations

Yeh

Cale

Jaru-Ampornpan

et al. 2006

“…While the present study showed that the T47I mutation significantly decreased Gag protein expression by a plasmid, we and others did not observe an associated defect in the level of virus production when using full-length provirus plasmids (data not shown) (29,33). This discordance in findings might be attributable to differences in the experimental systems used for these studies.…”

Section: Discussioncontrasting

confidence: 54%

“…In fact, recent studies have demonstrated that specific residues of this epitope are required for optimal viral replication (29,33). Therefore, structural constraints may limit SHIV-89.6P from mutating away from p11C, C-M-specific CTL recognition.…”

mentioning

confidence: 99%

Simian-Human Immunodeficiency Virus Escape from Cytotoxic T-Lymphocyte Recognition at a Structurally Constrained Epitope

Peyerl

Barouch

Yeh

et al. 2003

Virus-specific cytotoxic T lymphocytes (CTL) exert intense selection pressure on replicating simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) in infected individuals. The immunodominant Mamu-A * 01-restricted Gag p11C, C-M epitope is highly conserved among all sequenced isolates of SIV and therefore likely is structurally constrained. The strategies used by virus isolates to mutate away from an immunodominant epitope-specific CTL response are not well defined. Here we demonstrate that the emergence of a position 2 p11C, C-M epitope substitution (T47I) in a simian-human immunodeficiency virus (SHIV) strain 89.6P-infected Mamu-A * 01 ؉ monkey is temporally correlated with the emergence of a flanking isoleucine-to-valine substitution at position 71 (I71V) of the capsid protein. An analysis of the SIV and HIV-2 sequences from the Los Alamos HIV Sequence Database revealed a significant association between any position 2 p11C, C-M epitope mutation and the I71V mutation. The T47I mutation alone is associated with significant decreases in viral protein expression, infectivity, and replication, and these deficiencies are restored to wild-type levels with the introduction of the flanking I71V mutation. Together, these data suggest that a compensatory mutation is selected for in SHIV strain 89.6P to facilitate the escape of that virus from CTL recognition of the dominant p11C, C-M epitope.

“…The previously characterized clones of the 5Ј (p239SpSp5Ј) and 3Ј (p239SpE3Ј) halves of the SIVmac239 genome (AIDS Research and Reference Reagent Program) (34,47) were used to generate the full-length D(25)A PR SIVmac239 mutant exactly as described previously (49). The primers used to create this viral mutant made a (GAT3GCT) nucleotide substitution in codon 25 of the protease-encoding portion of pol.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation and Proteolytic Cleavage of Gag Proteins in Budded Simian Immunodeficiency Virus

Rue

Roos

Tarwater

et al. 2005

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