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, Richard A.; Goepfert, Paul; Allen, Susan; Hunter, Eric; Mulenga, Joseph; Kiepiela, Photini; Walker, Bruce D.; Goulder, Philip

doi:10.1128/jvi.00465-07

Cited by 201 publications

(150 citation statements)

References 33 publications

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“…Broadly neutralizing antibodies that target conserved viral epitopes may induce escape mutations in the virus that affect viral replicative fitness, as has been described for CD8 T cells (44)(45)(46). Structural and functional studies of the VRC01 class of antibodies indicate that they closely mimic the CD4 interaction with gp120 and bind to a conserved epitope that overlaps contact residues of the CD4 receptor (26,42,43,49,66).…”

Section: Discussionmentioning

confidence: 94%

“…Diminished viral replication after escape from T-cell immune pressure has been well documented for CD8 responses to the conserved Gag protein (44)(45)(46); however, it is less clear if the same is true for Env-targeting antibodies. It has been observed that mutations in CD4bs residues at the end of loop V5 that abrogate binding to anticore antibodies subsequently decrease viral fusion as well as viral infectivity (47), and there is evidence that in vivo antibody escape mutations in env can affect replication capacity (4,14,48).…”

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confidence: 99%

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HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies

Lynch

Wong

Tran

et al. 2015

J Virol

124

177

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Broadly neutralizing antibodies (bNAbs) have been isolated from selected HIV-1-infected individuals and shown to bind to conserved sites on the envelope glycoprotein (Env). However, circulating plasma virus in these donors is usually resistant to autologous isolated bNAbs, indicating that during chronic infection, HIV-1 can escape from even broadly cross-reactive antibodies. Here, we evaluate if such viral escape is associated with an impairment of viral replication. Antibodies of the VRC01 class target the functionally conserved CD4 binding site and share a structural mode of gp120 recognition that includes mimicry of the CD4 receptor. We examined naturally occurring VRC01-sensitive and -resistant viral strains, as well as their mutated sensitive or resistant variants, and tested point mutations in the backbone of the VRC01-sensitive isolate YU2. In several cases, VRC01 resistance was associated with a reduced efficiency of CD4-mediated viral entry and diminished viral replication. Several mutations, alone or in combination, in the loop D or ␤23-V5 region of Env conferred a high level of resistance to VRC01 class antibodies, suggesting a preferred escape pathway. We further mapped the VRC01-induced escape pathway in vivo using Envs from donor 45, from whom antibody VRC01 was isolated. Initial escape mutations, including the addition of a key glycan, occurred in loop D and were associated with impaired viral replication; however, compensatory mutations restored full replicative fitness. These data demonstrate that escape from VRC01 class antibodies can diminish viral replicative fitness, but compensatory changes may explain the limited impact of neutralizing antibodies during the course of natural HIV-1 infection. IMPORTANCESome antibodies that arise during natural HIV-1 infection bind to conserved regions on the virus envelope glycoprotein and potently neutralize the majority of diverse HIV-1 strains. The VRC01 class of antibodies blocks the conserved CD4 receptor binding site interaction that is necessary for viral entry, raising the possibility that viral escape from antibody neutralization might exert detrimental effects on viral function. Here, we show that escape from VRC01 class antibodies can be associated with impaired viral entry and replication; however, during the course of natural infection, compensatory mutations restore the ability of the virus to replicate normally.

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies

Lynch

Wong

Tran

et al. 2015

J Virol

124

177

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“…Positive selection pressure from the host immune system, which drives the selection of escape mutations (3,18), is responsible for some of these changes (12). However, others may be due to genetic drift or to changes in the amino acid sequence that compensate for any loss of core polypeptide function associated with the escape mutations (7,23). The full repertoire of common escape mutations in HBV polypeptides has not been defined, partly because the strong influences of both the viral genotype and host genetics on the immune response (26) make specific virus-host interactions difficult to identify in complex populations.…”

Section: Discussionmentioning

confidence: 99%

Associations between HLA Class I Alleles and Escape Mutations in the Hepatitis B Virus Core Gene in New Zealand-Resident Tongans

Abbott

Tsai

Leung

et al. 2010

J Virol

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The full repertoire of hepatitis B virus (HBV) peptides that bind to the common HLA class I molecules found in areas with a high prevalence of chronic HBV infection has not been determined. This information may be useful for designing immunotherapies for chronic hepatitis B. We identified amino acid residues under positive selection pressure in the HBV core gene by phylogenetic analysis of cloned DNA sequences obtained from HBV DNA extracted from the sera of Tongan subjects with inactive, HBeAg-negative chronic HBV infections. The repertoires of positively selected sites in groups of subjects who were homozygous for either HLA-B*4001 (n ‫؍‬ 10) or HLA-B*5602 (n ‫؍‬ 7) were compared. We identified 13 amino acid sites under positive selection pressure. A significant association between an HLA class I allele and the presence of nonsynonymous mutations was found at five of these sites. HLA-B*4001 was associated with mutations at E77 (P ‫؍‬ 0.05) and E113 (P ‫؍‬ 0.002), and HLA-B*5602 was associated with mutations at S21 (P ‫؍‬ 0.02). In addition, amino acid mutations at V13 (P ‫؍‬ 0.03) and E14 (P ‫؍‬ 0.01) were more common in the seven subjects with an HLA-A*02 allele. In summary, we have developed an assay that can identify associations between HLA class I alleles and HBV core gene amino acids that mutate in response to selection pressure. This is consistent with published evidence that CD8 ؉ T cells have a role in suppressing viral replication in inactive, HBeAg-negative chronic HBV infection. This assay may be useful for identifying the clinically significant HBV peptides that bind to common HLA class I molecules.The most potent nucleoside/nucleotide analogue drugs used to treat chronic hepatitis B reduce serum hepatitis B virus (HBV) DNA to undetectable levels in over 90% of subjects (5, 10). It was originally hoped that such a substantial reduction in viral titers would reverse T-cell tolerance for HBV antigens (17, 30) and lead to an immune response that permanently suppressed the virus, thus removing the need for expensive, lifelong drug therapy. However, HBeAg seroconversion rates of under 30% suggest that suppression of HBV replication is not sufficient to reverse the defects (4, 15) in the HBV peptidespecific CD8 ϩ T-cell compartment that occur in these patients. A therapeutic vaccine that stimulated a diverse repertoire of functional CD8 ϩ T cells could make a valuable contribution to management of chronic hepatitis B.The first step in designing a therapeutic vaccine that will suppress viral replication without exacerbating chronic hepatitis B (15) is to identify the HBV peptides that stimulate functional CD8 ϩ T cells by binding to the most common HLA class I alleles. These peptides may contribute to the antigen component of a vaccine and to the design of assays for use as correlates of immunity in trials of antiviral therapies. Although some of the HBV peptides that bind to four HLA-A alleles have been published (3,19,25,28), a much wider repertoire of peptide-HLA interactions needs to be identified. T...

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“…Intensive studies have identified several dominant epitope targets of CD8 T cells that are presented by these HLA alleles, and revealed that recognition of those epitopes in the HIV gag protein by CD8 T cells contributes to limiting the HIV viral load in plasma. The same studies have revealed a high frequency of escape mutations in those epitopes, with concomitant decrease in viral fitness, which also contributes to limiting the level of the HIV viral load (Crawford et al 2007, 2009; Goepfert et al 2008). That the observed mutations represent escape from CD8 T cell recognition is supported by a high rate of reversion to the ancestral sequence in the involved epitopes when HIV is transmitted to an individual lacking a protective HLA allele.…”

Section: 2 Antigenic Variation In Human Pathogensmentioning

confidence: 85%

“…Although antibodies and CD8 T cell responses are both directed against multiple HIV proteins, these two mechanisms of immunity have distinct effects, depending on the antigenic target: antibody responses drive antigenic variation of the HIV surface envelope glycoprotein (Hraber et al 2015), while CD8 T cell responses drive antigenic variation of the HIV internal gag protein (Crawford et al 2007, 2009; Goepfert et al 2008). …”

Section: 2 Antigenic Variation In Human Pathogensmentioning

confidence: 99%

Antigenic Variation and Immune Escape in the MTBC

Ernst

2017

Advances in Experimental Medicine and Biology

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Microbes that infect other organisms encounter host immune responses, and must overcome or evade innate and adaptive immune responses to successfully establish infection. Highly successful microbial pathogens, including M. tuberculosis, are able to evade adaptive immune responses (mediated by antibodies and/or T lymphocytes) and thereby establish long-term chronic infection. One mechanism that diverse pathogens use to evade adaptive immunity is antigenic variation, in which structural variants emerge that alter recognition by established immune responses and allow those pathogens to persist and/or to infect previously-immune hosts. Despite the wide use of antigenic variation by diverse pathogens, this mechanism appears to be infrequent in M. tuberculosis, as indicated by findings that known and predicted human T cell epitopes in this organism are highly conserved, although there are exceptions. These findings have implications for diagnostic tests that are based on measuring host immune responses, and for vaccine design and development.

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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 201 publications

References 33 publications

HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies

HIV-1 Fitness Cost Associated with Escape from the VRC01 Class of CD4 Binding Site Neutralizing Antibodies

Associations between HLA Class I Alleles and Escape Mutations in the Hepatitis B Virus Core Gene in New Zealand-Resident Tongans

Antigenic Variation and Immune Escape in the MTBC

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