Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study

Marichannegowda, Manukumar Honnayakanahalli; Zemil, Michelle; Wieczorek, Lindsay; Sanders-Buell, Eric; Bose, Meera; O'Sullivan, Anne Marie; King, David; Francisco, Leilani; Diaz-Mendez, Felisa; Setua, Saini; Chomont, Nicolas; Phanuphak, Nittaya; Ananworanich, Jintanat; Hsu, Denise; Vasan, Sandhya; Michael, Nelson L.; Eller, Leigh Anne; Tovanabutra, Sodsai; Tagaya, Yutaka; Robb, Merlin L.; Polonis, Victoria R.; Song, Hongshuo

doi:10.1016/j.ebiom.2023.104867

Cited by 3 publications

(4 citation statements)

References 38 publications

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“…While the enhanced CD4 virulence of the VB HIV-1 was considered as a “unfamiliar” mechanism associated with CCR5 tropism 4 , we hypothesize that the possibility that the VB variants could undergo early coreceptor switch in the infected individuals may also need to be explored. Our recent study, by tracking coreceptor switch in two participants in the RV217 acute infection cohort, provides evidence that coreceptor switch could be driven by autologous NAbs 32 . We hypothesized that coreceptor switch could function as a compensatory mechanism to maintain viral entry capacity, when the CCR5 usage is impaired by immune escape mutations driven by autologous NAbs 32 .…”

Section: Discussionmentioning

confidence: 98%

“…Our recent study, by tracking coreceptor switch in two participants in the RV217 acute infection cohort, provides evidence that coreceptor switch could be driven by autologous NAbs 32 . We hypothesized that coreceptor switch could function as a compensatory mechanism to maintain viral entry capacity, when the CCR5 usage is impaired by immune escape mutations driven by autologous NAbs 32 . Of note, both participants who underwent early coreceptor switch were infected by T/F viruses with unique glycan arrangement at the N295 and N332 positions (one T/F virus did not have the N332 or N334 glycan, and another T/F virus did not have the N295 glycan).…”

Section: Discussionmentioning

confidence: 98%

“…It is possible that the absence of the N295 and/or N332 glycans in the transmitted virus could expose the V3 loop to early humoral immune pressures, thereby increasing the chance of coreceptor switch. It is important to point out that, in all participants who underwent coreceptor switch in the RV217 cohort, the X4 variants existed at low frequency in plasma compared to the co-existing R5 viruses, which is likely due to their altered CD4 subset tropism towards the naïve and central memory CD4 subsets 32 . Because the sequences of the 17 VB variants are likely representing the predominant viral population in the plasma, the existence of low-frequency, CXCR4 variants in VB HIV-1 infected people could not be completely excluded.…”

Section: Discussionmentioning

confidence: 99%

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Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

Marichannegowda,

Heredia,

Wang

et al. 2024

Preprint

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HIV-1 is considered to become less susceptible to existing neutralizing antibodies over time. Our study on the virulent B (VB) HIV-1 identified genetic signatures responsible for immune escape from broadly neutralizing antibodies (bNAbs) targeting V1/V2 and V3 glycan epitopes. We found that the absence of N295 and N332 glycans in the high mannose patch, which are crucial for neutralization by V3 glycan bNAbs and are typically conserved in subtype B HIV-1, is a notable feature in more than half of the VB variants. Neutralization assays confirmed that the loss of these two glycans in VB HIV-1 leads to escape from V3 glycan bNAbs. Additionally, all VB variants we investigated have an insertion in V2, contributing to immune escape from V1/V2 bNAbs PG9 and PG16. These findings suggest potential co-evolution of HIV-1 virulence and antigenicity, underscoring the need to monitor both the pathogenicity and neutralization susceptibility of newly emerged HIV-1 strains.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

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Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

Marichannegowda,

Heredia,

Wang

et al. 2024

Preprint

Self Cite

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“…Co-receptor selection depends on properties of the V3 loop of gp120. A higher positive net charge in the V3 loop commonly leads to interaction with the CXCR4 co-receptor, whereas a neutral net charge leads to binding to the CCR5 co-receptor ( 31 – 33 ). The results of our study confirmed these features, with the CXCR4 receptor binding interface showing a more negative charge than the CCR5 binding site.…”

Section: Discussionmentioning

confidence: 99%

Distinct genetic clusters in HIV-1 CRF01_AE-infected patients induced variable degrees of CD4 ⁺ T-cell loss

Li,

Chen,

et al. 2024

mBio

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CRF01_AE strains have been shown to form multiple transmission clusters in China, and some clusters have disparate pathogenicity in Chinese men who have sex with men. This study focused on other CRF01_AE clusters prevalent in heterosexual populations. The CD4 + T-cell counts from both cross-section data in National HIV Molecular Epidemiology Survey and seropositive cohort data were used to evaluate the pathogenicity of the CRF01_AE clusters and other HIV-1 sub-types. Their mechanisms of pathogenicity were evaluated by co-receptor tropisms, predicted by genotyping and confirmed with virus isolate phenotyping, as well as inflammation parameters. Our research elucidated that individuals infected with CRF01_AE clusters 1 and 2 exhibited significantly lower baseline CD4 + T-cell counts and greater CD4 + T-cell loss in cohort follow-up, compared with other HIV-1 sub-types and CRF01_AE clusters. The increased pathogenesis of cluster 1 or 2 was associated with higher CXCR4 tropisms, higher inflammation/immune activation, and increased pyroptosis. The protein structure modeling analysis revealed that the envelope V3 loop of clusters 1 and 2 viruses is favorable for CXCR4 co-receptor usage. Imbedded with the most mutating reverse transcriptase, HIV-1 is one of the most variable viruses. CRF01_AE clusters 1 and 2 have been found to have evolved into more virulent strains in regions with predominant heterosexual infections. The virulent strains increased the pressure for early diagnosis and treatment in HIV patients. To save more lives, HIV-1 surveillance systems should be upgraded from serology and genotyping to phenotyping, which could support precision interventions for those infected by virulent viruses. IMPORTANCE Retroviruses swiftly adapt, employing error-prone enzymes for genetic and phenotypic evolution, optimizing survival strategies, and enhancing virulence levels. HIV-1 CRF01_AE has persistently undergone adaptive selection, and cluster 1 and 2 infections display lower counts and fast loss of CD4 + T cells than other HIV-1 sub-types and CRF01_AE clusters. Its mechanisms are associated with increased CXCR4 tropism due to an envelope structure change favoring a tropism shift from CCR5 to CXCR4, thereby shaping viral phenotype features and impacting pathogenicity. This underscores the significance of consistently monitoring HIV-1 genetic evolution and phenotypic transfer to see whether selection bias across risk groups alters the delicate balance of transmissible versus toxic trade-offs, since virulent strains such as CRF01_AE clusters 1 and 2 could seriously compromise the efficacy of antiviral treatment. Only through such early warning and diagnostic services can precise antiviral treatments be administered to those infected with more virulent HIV-1 strains.

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Transmission of highly virulent CXCR4 tropic HIV-1 through the mucosal route in an individual with a wild-type CCR5 genotype

Marichannegowda,

Setua,

Bose

et al. 2024

eBioMedicine

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Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study

Cited by 3 publications

References 38 publications

Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

Distinct genetic clusters in HIV-1 CRF01_AE-infected patients induced variable degrees of CD4 ⁺ T-cell loss

Transmission of highly virulent CXCR4 tropic HIV-1 through the mucosal route in an individual with a wild-type CCR5 genotype

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Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study

Cited by 3 publications

References 38 publications

Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

Genetic signatures in the highly virulent subtype B HIV-1 conferring immune escape to V1/V2 and V3 broadly neutralizing antibodies

Distinct genetic clusters in HIV-1 CRF01_AE-infected patients induced variable degrees of CD4 + T-cell loss

Transmission of highly virulent CXCR4 tropic HIV-1 through the mucosal route in an individual with a wild-type CCR5 genotype

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Product

Resources

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Distinct genetic clusters in HIV-1 CRF01_AE-infected patients induced variable degrees of CD4 ⁺ T-cell loss