Compensatory Mutation Partially Restores Fitness and Delays Reversion of Escape Mutation within the Immunodominant HLA-B*5703-Restricted Gag Epitope in Chronic Human Immunodeficiency Virus Type 1 Infection

Crawford, Hayley; Prado, Julia G.; Leslie, Alasdair; Hué, Stéphane; Honeyborne, Isobella; Reddy, Shabashini; Stok, Mary van der; Mncube, Zenele; Berthou, Christian; Rousseau, Christine; Mullins, James I.; Kaslow, RA; Goepfert, Paul; Allen, Suzanne; Hunter, Elizabeth; Mulenga, Joseph; Kiepiela, Photini; Walker, Bruce D.; Pjr., Goulder

doi:10.1128/jvi.02750-07

Cited by 80 publications

(140 citation statements)

References 0 publications

Supporting

Mentioning

127

Contrasting

Order By: Relevance

“…Moreover, many of those that do become selected are postulated to negatively affect virus fitness, as evidenced by rapid reversion to WT sequence when transmitted to hosts that lack the appropriate restriction element, or the requirement for co-selection of compensatory mutations that restore virus fitness (8,49,50). In a few cases, deleterious effects on virus fitness have been demonstrated directly in in vitro assays, using tissue culture cells or virus replicons (11,50,51). Consequently, a conclusion from these studies is that only a few mutations are selected because, despite their ability to evade CTL recognition, the vast majority negatively impact virus fitness.…”

Section: Discussionmentioning

confidence: 99%

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

Butler

Theodossis

Webb

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

Cytotoxic T lymphocyte escape occurs in many human infections, as well as mice infected with the JHM strain of mouse hepatitis virus, which exhibit CTL escape variants with mutations in a single epitope from the spike glycoprotein (S510). In all CTL epitopes prone to escape, only a subset of all potential variants is generally detected, even though many of the changes that are not selected would result in evasion of the T cell response. It is postulated that these unselected mutations significantly impair virus fitness. To define more precisely the basis for this preferential selection, we combine x-ray crystallographic studies of the MHC class I (Db)/S510 complexes with viral reverse genetics to identify a prominent TCR contact residue (tryptophan at position 4) prone to escape mutations. The data show that a mutation that is commonly detected in chronically infected mice (tryptophan to arginine) potently disrupts the topology of the complex, explaining its selection. However, other mutations at this residue, which also abrogate the CTL response, are never selected in vivo even though they do not compromise virus fitness in acutely infected animals or induce a significant de novo CTL response. Thus, while structural analyses of the S510/Db complex provide a strong basis for why some CTL escape variants are selected, our results also show that factors other than effects on virus fitness limit the diversification of CD8 T cell epitopes.

show abstract

Section: Discussionmentioning

confidence: 99%

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

Butler

Theodossis

Webb

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Previously described A163G and A163G/S165N variants (13,20) were most common in clade A1 (Table 1). In addition, the novel K162X substitution was present in clade A1.…”

Section: ϫ7mentioning

confidence: 99%

Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

McKinnon

Capiña

Peters

et al. 2009

J Virol

View full text Add to dashboard Cite

HLA-B*57-mediated selection pressure leads to a typical escape pathway in human immunodeficiency virus type 1 (HIV-1) CD8 epitopes such as TW10. Whether this T242N pathway is shared by all clades remains unknown. We therefore assessed the nature of HLA-B*57 selection in a large, observational Kenyan cohort where clades A1 and D predominate. While T242N was ubiquitous in clade D HLA-B*57 ؉ subjects, this mutation was rare (15%) in clade A1. Instead, P243T and I247L were selected by clade A1-infected HLA-B*57 subjects but not by HLA-B*5801 ؉ subjects. Our data suggest that clade A1 consensus proline at Gag residue 243 might represent an inherent block to T242N escape in clade A1. We confirmed immunologically that P243T and I247L likely represent escape mutations. HLA-B*57 evolution also differed between clades in the KF11 and IW9 epitopes. A better understanding of clade-specific evolution is important for the development of HIV vaccines in regions with multiple clades.

show abstract

“…In this study, we investigate infections with attenuated viruses by letting the founder virus start with a low fitness due to a preexisting escape mutation accompanied by an imperfect compensatory mutation (see Materials and Methods). This crippled virus simulates the T242N mutation of HLA-B57, which is known to have compensatory mutations up and downstream of the epitope, which only partially rescues the deleterious defect of T242N (48). We compare the evolutionary dynamics of a wild-type virus, with Fig.…”

Section: Infection With An Attenuated Virus Decreases the Rate Of Hivmentioning

confidence: 99%

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

Deutekom

Wijnker

Boer

2013

The Journal of Immunology

View full text Add to dashboard Cite

During the first months of HIV infection, the virus typically evolves several immune escape mutations. These mutations are found in epitopes in viral proteins and reduce the impact of the CD8+ T cells specific for these epitopes. Recent data show that only a subset of the epitopes escapes, that most of these escapes evolve early, and that the rate of immune escape slows down considerably. To investigate why the evolution of immune escape slows down over the time of infection, we have extended a consensus mathematical model to allow several immune responses to control the virus together. In the extended model, most escapes also occur early, and the immune escape rate becomes small later, and typically only a minority of the epitopes escape. We show that escaping one of the many immune responses provides little advantage after viral setpoint has been approached because the total killing rate hardly depends on the breadth of the immune response. If the breadth of the immune response slowly wanes during disease progression, the model predicts an increase in the rate of immune escape at late stages of infection. Overall, the most striking prediction of the model is that HIV evolves a small number of immune escapes, in both relative and absolute terms, when the CTL immune response is broad.

show abstract

Compensatory Mutation Partially Restores Fitness and Delays Reversion of Escape Mutation within the Immunodominant HLA-B*5703-Restricted Gag Epitope in Chronic Human Immunodeficiency Virus Type 1 Infection

Cited by 80 publications

References 0 publications

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

Structural and Biological Basis of CTL Escape in Coronavirus-Infected Mice

Clade-Specific Evolution Mediated by HLA-B*57/5801 in Human Immunodeficiency Virus Type 1 Clade A1 p24

The Rate of Immune Escape Vanishes When Multiple Immune Responses Control an HIV Infection

Contact Info

Product

Resources

About