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Jayanta Bhattacharya
International AIDS Vaccine Initiative and Translational Health Science & Technology Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1531-3822
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Background. The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121.
Results. We found significant variations in the susceptibility of Indian clade C to these four bnAbs and were found to be distinct to that observed with that of African subtype C based on the existing datasets and were also found to be concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed overtime with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999-2016. Our data was found to be distinct from what was observed in case of African HIV-1 subtype C. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber (www.hiv.lanl.gov), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage.
Conclusions. Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrants the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.
Keywords
HIV-1, clade C, neutralizing antibodies, envelope, VRC01, CAP256-VRC26.25, PGDM1400, PGT121, India
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- FIG.S1.tif
Figure S1. Comparison of trend in bnAb sensitivity of African clade C across time against VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. Scatter plots of IC50 values for Env-pseudotyped viruses reported in the CATNAP database were grouped as 1990-2000, 2001-2005 and 2006-2010 for envs from Pan-Africa. Data points were color-coded based on the disease stage at sampling of the respective viruses. IC50 value of 5µg/ml was considered as a threshold of neutralization sensitivity. Statistical assessment of increase in IC50 values was performed with Jonckheere-Terpstra test.
- TABLES1FINAL.docx
Table S1. History of year of collection of clinical samples, disease stages and env genetic properties.
- TABLES2Final.docx
Table S2. Mapping key amino acid substitutions associated with resistance to the bnAbs.
- Table1.docx
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CURRENT STATUS: Under Review
Version 1
Posted 19 Jan, 2021
No community comments so far
Review #2 received
Received 10 Mar, 2021
Editorial decision: Minor revision
On 10 Mar, 2021
Reviewer #2 agreed
On 16 Feb, 2021
Review #1 received
Received 30 Jan, 2021
Reviewers invited
Invitations sent on 19 Jan, 2021
Reviewer #1 agreed
On 19 Jan, 2021
Editor assigned
On 14 Jan, 2021
Submission checks complete
On 14 Jan, 2021
Editor invited
On 14 Jan, 2021
First submitted
On 13 Jan, 2021
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Subject Areas
Virology
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This preprint is under consideration at Retrovirology. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Jayanta Bhattacharya
International AIDS Vaccine Initiative and Translational Health Science & Technology Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-1531-3822
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 19 Jan, 2021
No community comments so far
Review #2 received
Received 10 Mar, 2021
Editorial decision: Minor revision
On 10 Mar, 2021
Reviewer #2 agreed
On 16 Feb, 2021
Review #1 received
Received 30 Jan, 2021
Reviewers invited
Invitations sent on 19 Jan, 2021
Reviewer #1 agreed
On 19 Jan, 2021
Editor assigned
On 14 Jan, 2021
Submission checks complete
On 14 Jan, 2021
Editor invited
On 14 Jan, 2021
First submitted
On 13 Jan, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Virology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background. The potential use of the broadly neutralizing monoclonal antibodies (bnAbs) towards prophylaxis and treatment to HIV-1 is currently being explored. While a number of promising bnAbs have been discovered and few of them have progressed towards clinical development, their extent of neutralization coverage with respect to global HIV-1 variants given the existence of genetically distinct subtypes and recombinants circulating globally is not clearly known. In the present study, we examined the variation in the neutralization susceptibility of pseudoviruses expressing 71 full length primary HIV-1 subtype C envs obtained from limited cross-sectional individuals over different time points against four bnAbs that target gp120 with distinct specificities: VRC01, CAP256-VRC26.25, PGDM1400 and PGT121.
Results. We found significant variations in the susceptibility of Indian clade C to these four bnAbs and were found to be distinct to that observed with that of African subtype C based on the existing datasets and were also found to be concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed overtime with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999-2016. Our data was found to be distinct from what was observed in case of African HIV-1 subtype C. However, inconsistent trend in neutralization susceptibility was observed, when pseudoviruses expressing envs obtained from three followed up individuals were examined. Finally, through predictive analysis of the 98 Indian subtype C including those assessed in the present study by employing additive model implemented in CombiNAber (www.hiv.lanl.gov), we observed two possibilities where combinations of three bnAbs (VRC01/CAP56-VRC26.25/PGT121 and PGDM1400/CAP256-VRC26.25/PGT121) could achieve near 100% neutralization coverage.
Conclusions. Our findings not only indicate disparate intra-clade C genetic vis-à-vis neutralization diversities but also warrants the need for more comprehensive study using additional isolates towards comparing inter and intra-clade neutralization diversities which will be necessary for selecting the bnAb combinations suitable for optimal coverage of the region-specific HIV-1 circulating subtypes. Expanding these efforts is imperative for designing efficacious bnAb based intervention strategies for India as well as subtype C in general.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- FIG.S1.tif
Figure S1. Comparison of trend in bnAb sensitivity of African clade C across time against VRC01, CAP256-VRC26.25, PGDM1400 and PGT121. Scatter plots of IC50 values for Env-pseudotyped viruses reported in the CATNAP database were grouped as 1990-2000, 2001-2005 and 2006-2010 for envs from Pan-Africa. Data points were color-coded based on the disease stage at sampling of the respective viruses. IC50 value of 5µg/ml was considered as a threshold of neutralization sensitivity. Statistical assessment of increase in IC50 values was performed with Jonckheere-Terpstra test.
- TABLES1FINAL.docx
Table S1. History of year of collection of clinical samples, disease stages and env genetic properties.
- TABLES2Final.docx
Table S2. Mapping key amino acid substitutions associated with resistance to the bnAbs.
- Table1.docx
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