Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus

Sather, D. Noah; Carbonetti, Sara; Kehayia, Jenny; Kraft, Zane; Mikell, Iliyana; Scheid, Johannes F.; Klein, Florian; Stamatatos, Leonidas

doi:10.1128/jvi.01893-12

Cited by 41 publications

(51 citation statements)

References 48 publications

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“…Molecular cloning of HIV-1 genomes is labor intensive and thus limits the number of IMCs that can reasonably be characterized. Moreover, predicting which viral genomes are functional in chronically infected individuals is challenging, because immune escape mutations frequently incur fitness costs (38)(39)(40)(41)(42)(43)(44)(45). Virus isolation represents an alternative to cloning, but bulk cultures cannot account for the biological variation of individual quasispecies members.…”

Section: Generation Of Limiting Dilution Hiv-1 Isolates From Sexual Tmentioning

confidence: 99%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

129

180

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Sexual transmission of HIV-1 is an inefficient process, with only one or few variants of the donor quasispecies establishing the new infection. A critical, and as yet unresolved, question is whether the mucosal bottleneck selects for viruses with increased transmission fitness. Here, we characterized 300 limiting dilution-derived virus isolates from the plasma, and in some instances genital secretions, of eight HIV-1 donor and recipient pairs. Although there were no differences in the amount of virion-associated envelope glycoprotein, recipient isolates were on average threefold more infectious (P = 0.0001), replicated to 1.4-fold higher titers (P = 0.004), were released from infected cells 4.2-fold more efficiently (P < 0.00001), and were significantly more resistant to type I IFNs than the corresponding donor isolates. Remarkably, transmitted viruses exhibited 7.8-fold higher IFNα2 (P < 0.00001) and 39-fold higher IFNβ (P < 0.00001) half-maximal inhibitory concentrations (IC 50 ) than did donor isolates, and their odds of replicating in CD4 + T cells at the highest IFNα2 and IFNβ doses were 35-fold (P < 0.00001) and 250-fold (P < 0.00001) greater, respectively. Interestingly, pretreatment of CD4 + T cells with IFNβ, but not IFNα2, selected donor plasma isolates that exhibited a transmitted virus-like phenotype, and such viruses were also detected in the donor genital tract. These data indicate that transmitted viruses are phenotypically distinct, and that increased IFN resistance represents their most distinguishing property. Thus, the mucosal bottleneck selects for viruses that are able to replicate and spread efficiently in the face of a potent innate immune response.

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Section: Generation Of Limiting Dilution Hiv-1 Isolates From Sexual Tmentioning

confidence: 99%

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Iyer

Bibollet-Ruche

Sherrill-Mix

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

129

180

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“…The virus and B cells continue to mutate in response to each other (10,11), and this coevolution leads to various levels of cross-reactive serum neutralizing activity among HIV-1-infected individuals and, in a limited number of cases, the development of broad and potent neutralizing antibody responses (12)(13)(14)(15)(16)(17). However, even among donors with broadly neutralizing sera, the circulating plasma virus generally continues to escape from autologous serum neutralization, thus allowing persistent viral replication (10,13,(18)(19)(20).…”

mentioning

confidence: 99%

“…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). Sather and colleagues studied one donor, VC10042, whose sera contained broadly neutralizing activity directed against the CD4bs and demonstrated that viral escape from this response negatively impacted viral replication in some autologous viral strains (19). These data suggest that viral escape from a polyclonal response could decrease viral replicative fitness, but the impact of viral escape from a specific bNAb, such as VRC01, has not been fully addressed.…”

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

123

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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“…espite the ability of HIV-1 to evade the antibody response, some HIV-1-infected individuals develop high titers of broadly neutralizing antibodies (bNAbs) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). Since 2009, thanks to the development of single-cell-based antibody cloning techniques, a large number of monoclonal bNAbs with outstanding potencies have been isolated from such individuals (12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Drift of the HIV-1 Envelope Glycoprotein gp120 toward Increased Neutralization Resistance over the Course of the Epidemic: a Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies

Bouvin-Pley

Morgand

Meyer

et al. 2014

J Virol

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Extending our previous analyses to the most recently described monoclonal broadly neutralizing antibodies (bNAbs), we confirmed a drift of HIV-1 clade B variants over 2 decades toward higher resistance to bNAbs targeting almost all the identified gp120-neutralizing epitopes. In contrast, the sensitivity to bNAbs targeting the gp41 membrane-proximal external region remained stable, suggesting a selective pressure on gp120 preferentially. Despite this evolution, selected combinations of bNAbs remain capable of neutralizing efficiently most of the circulating variants.

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Broadly Neutralizing Antibodies Developed by an HIV-Positive Elite Neutralizer Exact a Replication Fitness Cost on the Contemporaneous Virus

Cited by 41 publications

References 48 publications

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

Resistance to type 1 interferons is a major determinant of HIV-1 transmission fitness

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

Drift of the HIV-1 Envelope Glycoprotein gp120 toward Increased Neutralization Resistance over the Course of the Epidemic: a Comprehensive Study Using the Most Potent and Broadly Neutralizing Monoclonal Antibodies

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