Neutralization diversity of HIV-1 Indian subtype C envelopes obtained from cross sectional and followed up individuals against broadly neutralizing monoclonal antibodies having distinct gp120 specificities

Abstract 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 a 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. These variations were found to be distinct to that observed in African subtype C based on the existing datasets and concordant with their sequence diversity. Trend analysis indicated an increasing neutralization resistance observed over time with CAP25-VRC26.25, PGDM1400 and PGT121 when tested on pseudoviruses expressing envs obtained from 1999 to 2016. 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 (http://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 warrant 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.

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Neutralization Diversity of HIV-1 Indian Subtype C Envelopes Obtained From Cross Sectional and Followed up Individuals Against Broadly Neutralizing Monoclonal Antibodies Having Distinct Gp120 Specificities

10.21203/rs.3.rs-148517/v1 ◽

2021 ◽

Author(s):

Ranajoy Mullick ◽

Jyoti Sutar ◽

Nitin Hingankar ◽

Suprit Deshpande ◽

Madhuri Thakar ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Additive Model ◽

Clinical Development ◽

Intervention Strategies ◽

Subtype C ◽

Cross Sectional ◽

Clade C ◽

Potential Use ◽

Hiv 1 ◽

Comprehensive Study

Abstract 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.

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Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

10.1101/2020.09.25.312942 ◽

2020 ◽

Author(s):

Susana Posada-Céspedes ◽

Gert Van Zyl ◽

Hesam Montazeri ◽

Jack Kuipers ◽

Soo-Yon Rhee ◽

...

Keyword(s):

Drug Resistance ◽

Genotype Data ◽

Resistance Mutations ◽

Subtype C ◽

Cross Sectional ◽

Data Set ◽

Hiv Drug Resistance ◽

Subtype B ◽

Hiv 1 ◽

Temporal Ordering

AbstractAlthough combination antiretoviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Here, we present a methodology for the comparison of mutational pathways in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational pathways from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models on a large number of resistance mutations and develop a statistical test to assess differences in the inferred mutational pathways between two groups. We apply this method to the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional data set of South African individuals living with HIV-1 subtype C, as well as a genotype data set of subtype B infections derived from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. Our results also show that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Furthermore, the maximum likelihood mutational networks for subtypes B and C share only 7 edges (Jaccard distance 0.802) and imply many different evolutionary pathways. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational pathways between any two groups.Author summaryThere is a disparity in the distribution of infections by HIV-1 subtype in the world. Subtype B is predominant in America, Western Europe and Australia, and most therapeutic strategies are based on research and clinical studies on this subtype. However, non-B subtypes represent the majority of global HIV-1 infections; e.g., subtype C alone accounts for nearly half of all HIV-1 infections. We present a statistical framework enabling the comparison of patterns of accumulating mutations in different HIV-1 subtypes. Specifically, we study lopinavir resistance pathways in HIV-1 subtypes B versus C, but the methodology can be generally applied to compare the temporal ordering of genetic events in different subgroups.

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Comparing mutational pathways to lopinavir resistance in HIV-1 subtypes B versus C

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008363 ◽

2021 ◽

Vol 17 (9) ◽

pp. e1008363

Author(s):

Susana Posada-Céspedes ◽

Gert Van Zyl ◽

Hesam Montazeri ◽

Jack Kuipers ◽

Soo-Yon Rhee ◽

...

Keyword(s):

Drug Resistance ◽

Strong Support ◽

Monte Carlo Sampling ◽

Resistance Mutations ◽

Subtype C ◽

Cross Sectional ◽

Data Set ◽

Hiv Drug Resistance ◽

Subtype B ◽

Hiv 1

Although combination antiretroviral therapies seem to be effective at controlling HIV-1 infections regardless of the viral subtype, there is increasing evidence for subtype-specific drug resistance mutations. The order and rates at which resistance mutations accumulate in different subtypes also remain poorly understood. Most of this knowledge is derived from studies of subtype B genotypes, despite not being the most abundant subtype worldwide. Here, we present a methodology for the comparison of mutational networks in different HIV-1 subtypes, based on Hidden Conjunctive Bayesian Networks (H-CBN), a probabilistic model for inferring mutational networks from cross-sectional genotype data. We introduce a Monte Carlo sampling scheme for learning H-CBN models for a larger number of resistance mutations and develop a statistical test to assess differences in the inferred mutational networks between two groups. We apply this method to infer the temporal progression of mutations conferring resistance to the protease inhibitor lopinavir in a large cross-sectional cohort of HIV-1 subtype C genotypes from South Africa, as well as to a data set of subtype B genotypes obtained from the Stanford HIV Drug Resistance Database and the Swiss HIV Cohort Study. We find strong support for different initial mutational events in the protease, namely at residue 46 in subtype B and at residue 82 in subtype C. The inferred mutational networks for subtype B versus C are significantly different sharing only five constraints on the order of accumulating mutations with mutation at residue 54 as the parental event. The results also suggest that mutations can accumulate along various alternative paths within subtypes, as opposed to a unique total temporal ordering. Beyond HIV drug resistance, the statistical methodology is applicable more generally for the comparison of inferred mutational networks between any two groups.

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Determinants in V2C2 region of HIV-1 clade C primary envelopes conferred altered neutralization susceptibilities to IgG1b12 and PG9 monoclonal antibodies in a context-dependent manner

Virology ◽

10.1016/j.virol.2014.06.018 ◽

2014 ◽

Vol 462-463 ◽

pp. 266-272 ◽

Cited By ~ 1

Author(s):

Shilpa Patil ◽

Ipsita Choudhary ◽

Nakul K. Chaudhary ◽

Rajesh Ringe ◽

Manish Bansal ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Dependent Manner ◽

Clade C ◽

Context Dependent ◽

Hiv 1

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Antigenicity and immunogenicity of a novel, acute HIV-1 Tanzanian subtype C gp145 envelope protein for clinical development

Retrovirology ◽

10.1186/1742-4690-9-s2-p323 ◽

2012 ◽

Vol 9 (S2) ◽

Cited By ~ 1

Author(s):

V Polonis ◽

L Wieczorek ◽

V Kalyanaraman ◽

G Matyas ◽

S Whitney ◽

...

Keyword(s):

Envelope Protein ◽

Clinical Development ◽

Subtype C ◽

Acute Hiv ◽

Hiv 1

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Insensitivity of Paediatric HIV-1 Subtype C Viruses to Broadly Neutralising Monoclonal Antibodies Raised against Subtype B

PLoS Medicine ◽

10.1371/journal.pmed.0030255 ◽

2006 ◽

Vol 3 (7) ◽

pp. e255 ◽

Cited By ~ 64

Author(s):

Elin Solomonovna Gray ◽

Tammy Meyers ◽

Glenda Gray ◽

David Charles Montefiori ◽

Lynn Morris

Keyword(s):

Monoclonal Antibodies ◽

Subtype C ◽

Paediatric Hiv ◽

Subtype B ◽

Hiv 1

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Insights into the Activity of Second-Generation Maturation Inhibitors against HIV Clade C

Proceedings ◽

10.3390/proceedings2020050060 ◽

2020 ◽

Vol 50 (1) ◽

pp. 60

Author(s):

Dibya Ghimire ◽

Yuvraj KC ◽

Ritu Gaur

Keyword(s):

Second Generation ◽

Novel Mutation ◽

Hiv Infections ◽

Binding Pocket ◽

Resistance Mutations ◽

Subtype C ◽

Maturation Inhibitor ◽

Clade C ◽

Ic50 Values ◽

Hiv 1

Maturation inhibitors represent a new underdeveloped class of antiretroviral agents that block virus maturation by binding to the target of protease (PR)-Gag precursor (Pr55Gag). Development of a maturation inhibitor is based on a number of small molecules that are capable of blocking the cleavage event between p24-CA and spacer peptide 1. The bulk of the literature on HIV antiretroviral therapy and drug resistance has primarily been derived from HIV-1B, and relatively less is known about the context of HIV-1C that is responsible for more than 95% of HIV infections of India and half of these infections globally. We and others have shown that the presence of maturation inhibitor resistance mutations would make HIV-1B particles either less fit or dependent on these drugs to replicate. By contrast, it is unclear how HIV-1C would naturally acquire these mutations yet remain replication competent in the absence of the selective pressure of maturation inhibitors. Bevirimat, the first-in-class MI, was found to be inactive against HIV-C due to polymorphisms in the SP1 region. We have identified novel second generation of HIV maturation inhibitors with high potency against HIV clade C (IC50 values in the low nM range). The mutations identified during selection experiments revealed the putative binding pocket of these compounds on HIV-1 subtype C Gag. While working on the role of CA-C terminal domain (CA-CTD) domain in HIV-1 Gag assembly and release, we have found that core glycine-rich residues of the β-turn motif are crucial in Gag-membrane binding, multimerization, and assembly. Furthermore, we have identified a novel mutation in CA-CTD that is dependent on both classes of MIs. In conclusion, our studies provide insights into the mechanistic action of MIs on HIV-1 Gag processing and stabilization.

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Immunogenicity of HIV-1 Vaccines Expressing Chimeric Envelope Glycoproteins on the Surface of Pr55 Gag Virus-Like Particles

Vaccines ◽

10.3390/vaccines8010054 ◽

2020 ◽

Vol 8 (1) ◽

pp. 54

Author(s):

Rosamund Chapman ◽

Michiel van Diepen ◽

Shireen Galant ◽

Elizabeth Kruse ◽

Emmanuel Margolin ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Neutralizing Antibodies ◽

Recombinant Dna ◽

Neutralizing Antibody ◽

Tier 2 ◽

Subtype C ◽

Spike Density ◽

Virus Like Particles ◽

Env Antigens ◽

Hiv 1

The HIV-1 envelope glycoprotein (Env) is present on the surface of the virion at a very low density compared to most other enveloped viruses. Substitution of various parts of the stalk domain of Env (gp41) with the corresponding elements from other viral glycoproteins has been shown to increase Env spike density on the cell membrane and surface of virus-like particles (VLPs). In this study, chimeric Env antigens were generated by replacing the transmembrane and cytoplasmic domains of HIV-1 Env with the corresponding regions from the influenza H5 hemagglutinin (HA) (gp140HA2tr) and by replacing the entire gp41 region of Env with the HA2 subunit of HA (gp120HA2). Recombinant DNA and modified vaccinia Ankara (MVA) vaccines expressing HIV-1 subtype C mosaic Gag and gp150 Env or either of the chimeras were generated. Surprisingly, no significant differences were found in the levels of expression of gp150 Env or either of the chimeras on the surface of cells or on Gag VLPs. Differences were, however, observed in the binding of different monoclonal antibodies to the HIV-1 Env. Monoclonal antibodies, which recognized a V1 / V2 quaternary epitope at the tip of the native Env trimer, bound gp150 and gp140HA2tr chimera but failed to bind to the gp120HA2 chimera. Autologous Tier 2 neutralizing antibodies (NAbs) were produced by rabbits inoculated with DNA and MVA vaccines expressing the gp140HA2tr chimera or gp150 Env, but not those immunized with the gp120HA2 Env. These results showed that the addition of an HA2 stalk to HIV-1 gp120 did not improve immunogenicity, but rather that the full-length gp150 was required for optimal presentation of epitopes for the elicitation of a neutralizing antibody response to HIV-1.

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