Altered HIV-1 Gag Protein Interactions with Cyclophilin A (CypA) on the Acquisition of H219Q and H219P Substitutions in the CypA Binding Loop

Gatanaga, Hiroyuki; Das, Debananda; Suzuki, Yoshiaki; Yeh, Damaris D.; Hussain, Khaja Azhar; Ghosh, Arun K.; Mitsuya, Hiroaki

doi:10.1074/jbc.m505920200

Cited by 48 publications

(61 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gag residues H 219 and I 223 in the CypA-binding loop have been shown to interact with CypA (3), and therefore, TW10-associated changes in the loop region may directly affect binding to CypA. Our results are consistent with those of recent reports demonstrating that the H 219 Q mutation alters capsid interactions with CypA, as well as data indicating that the QVI mutations diminished viral sensitivity to owl monkey Trim5-CypA and CsA (23,33). Together, these data suggest that modest differences in CypA interactions by TW10 escape variants result in a postentry capsid defect in primary cells and Jurkat T cells that can be enhanced by the addition of CsA.…”

Section: Discussionsupporting

confidence: 83%

“…The precise effects of this interaction are not well understood, but it is likely that CypA alters capsid stability (31,36), regulates viral uncoating (33), and/or prevents host restriction factor recognition (62). Therefore, the variable phenotype observed between Jurkat and CEM T cells may be due to differences in the expression of CypA or another protein related to these processes.…”

Section: Discussionmentioning

confidence: 99%

“…Binding of the capsid to target cell protein CypA is critical for efficient viral replication (19,20,39), likely through alteration of capsid stability (31,36), regulation of the viral uncoating process (33), or prevention of host restriction factor recognition (62). These observations prompted us to examine whether secondary capsid mutations associated with CTL escape in TW10 altered this critical viral protein-host protein interaction, thus compromising the ability of HIV-1 to replicate efficiently.…”

Section: Cd8mentioning

confidence: 99%

See 2 more Smart Citations

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Brockman

Schneidewind

Lahaie

et al. 2007

J Virol

243

338

View full text Add to dashboard Cite

Certain histocompatibility leukocyte antigen (HLA) alleles are associated with improved clinical outcomes for individuals infected with human immunodeficiency virus type 1 (HIV-1), but the mechanisms for their effects remain undefined. An early CD8؉ T-cell escape mutation in the dominant HLA-B57-restricted Gag epitope TW10 (TSTLQEQIGW) has been shown to impair HIV-1 replication capacity in vitro. We demonstrate here that this T 242 N substitution in the capsid protein is associated with upstream mutations at residues H 219 , I 223 , and M 228 in the cyclophilin A (CypA)-binding loop in B57؉ individuals with progressive disease. In an independent cohort of epidemiologically linked transmission pairs, the presence of these substitutions in viruses encoding T 242 N was associated with significantly higher plasma viremia in donors, further suggesting that these secondary mutations compensated for the replication defect of T 242 N. Using NL4-3 constructs, we illustrate the ability of these CypA loop changes to partially restore replication of the T 242 N variant in vitro. Notably, these mutations also enhanced viral resistance to the drug cyclosporine A, indicating a reduced dependence of the compensated virus on CypA that is normally essential for optimal infectivity. Therefore, mutations in TW10 allow HIV-1 to evade a dominant early CD8 ؉ T-cell response, but the benefits of escape are offset by a defect in capsid function. These data suggest that TW10 escape variants undergo a postentry block that is partially overcome by changes in the CypA-binding loop and identify a mechanism for an HIV-1 fitness defect that may contribute to the slower disease progression associated with HLA-B57.

show abstract

Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Cd8mentioning

confidence: 99%

See 1 more Smart Citation

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Brockman

Schneidewind

Lahaie

et al. 2007

J Virol

243

338

View full text Add to dashboard Cite

show abstract

“…Moreover, for B57-TW10, several independent compensatory mutations have been described, each of which only partially restores replication capacity (7). Notably, however, none of these compensatory mutations appears absolutely necessary for development of T 242 N (7), and at least one of the compensatory mutations does not confer a defect on viral replication when present in isolation (15). Therefore, it is likely that T 242 N reverts irrespective of the presence of compensatory mutations.…”

mentioning

confidence: 99%

Transmission and Long-Term Stability of Compensated CD8 Escape Mutations

Schneidewind

Brumme

et al. 2009

J Virol

View full text Add to dashboard Cite

Human immunodeficiency virus effectively evades CD8؉ T-cell responses through the development of CD8 escape mutations. Recent reports documenting reversion of transmitted mutations and the impact of specific escape mutations upon viral replication suggest that complex forces limit the accumulation of CD8 escape mutations at the population level. However, the presence of compensatory mutations capable of alleviating the impact of CD8 escape mutations on replication capacity may enable their persistence in an HLA-mismatched host. Herein, we illustrate the long-term stability of stereotypic escape mutations in the immunodominant HLA-B27-restricted epitope KK10 in p24/Gag following transmission when accompanied by a specific compensatory mutation.

show abstract

“…The L75R and H219Q mutations also improved the replication fitness of the wild-type laboratory strain NL4-3 but did not allow replication in the presence of protease inhibitors (68). It is of interest that the H219Q mutation is in the cyclophilin A binding loop and that the replication advantage conferred by it was influenced by the cyclophilin A concentration of different cell types (67), suggesting that gag-cyclophilin A interactions are important for HIV-1 replication fitness. There are several additional examples of mutations outside of protease cleavage sites that improve the fitness of protease inhibitor-resistant viruses in the absence of cleavage site mutations, indicating that the coevolution of gag and protease is very complex (124).…”

Section: Extragenic Interactionsmentioning

confidence: 99%

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Dykes

Demeter

2007

Clin Microbiol Rev

View full text Add to dashboard Cite

SUMMARY The relative fitness of a variant, according to population genetics theory, is that variant's relative contribution to successive generations. Most drug-resistant human immunodeficiency virus type 1 (HIV-1) variants have reduced replication fitness, but at least some of these deficits can be compensated for by the accumulation of second-site mutations. HIV-1 replication fitness also appears to influence the likelihood of a drug-resistant mutant emerging during treatment failure and is postulated to influence clinical outcomes. A variety of assays are available to measure HIV-1 replication fitness in cell culture; however, there is no agreement regarding which assays best correlate with clinical outcomes. A major limitation is that there is no high-throughput assay that incorporates an internal reference strain as a control and utilizes intact virus isolates. Some retrospective studies have demonstrated statistically significant correlations between HIV-1 replication fitness and clinical outcomes in some patient populations. However, different studies disagree as to which clinical outcomes are most closely associated with fitness. This may be in part due to assay design, sample size limitations, and differences in patient populations. In addition, the strength of the correlations between fitness and clinical outcomes is modest, suggesting that, at present, it would be difficult to utilize these assays for clinical management.

show abstract

Altered HIV-1 Gag Protein Interactions with Cyclophilin A (CypA) on the Acquisition of H219Q and H219P Substitutions in the CypA Binding Loop

Cited by 48 publications

References 35 publications

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Escape and Compensation from Early HLA-B57-Mediated Cytotoxic T-Lymphocyte Pressure on Human Immunodeficiency Virus Type 1 Gag Alter Capsid Interactions with Cyclophilin A

Transmission and Long-Term Stability of Compensated CD8 Escape Mutations

Clinical Significance of Human Immunodeficiency Virus Type 1 Replication Fitness

Contact Info

Product

Resources

About