TY - JOUR
T1 - Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting
T2 - the RV217 acute infection cohort study
AU - Marichannegowda, Manukumar Honnayakanahalli
AU - Zemil, Michelle
AU - Wieczorek, Lindsay
AU - Sanders-Buell, Eric
AU - Bose, Meera
AU - O'Sullivan, Anne Marie
AU - King, David
AU - Francisco, Leilani
AU - Diaz-Mendez, Felisa
AU - Setua, Saini
AU - Chomont, Nicolas
AU - Phanuphak, Nittaya
AU - Ananworanich, Jintanat
AU - Hsu, Denise
AU - Vasan, Sandhya
AU - Michael, Nelson L.
AU - Eller, Leigh Anne
AU - Tovanabutra, Sodsai
AU - Tagaya, Yutaka
AU - Robb, Merlin L.
AU - Polonis, Victoria R.
AU - Song, Hongshuo
N1 - Publisher Copyright:
© 2023 The Author(s)
PY - 2023/12
Y1 - 2023/12
N2 - Background: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. Methods: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. Findings: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. Interpretations: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. Funding: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.
AB - Background: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. Methods: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. Findings: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. Interpretations: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. Funding: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.
KW - CD4 subset
KW - Coreceptor switch
KW - HIV-1
KW - Immune evasion
KW - Pathogenesis
UR - http://www.scopus.com/inward/record.url?scp=85176132256&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2023.104867
DO - 10.1016/j.ebiom.2023.104867
M3 - Article
C2 - 37939456
AN - SCOPUS:85176132256
SN - 2352-3964
VL - 98
JO - eBioMedicine
JF - eBioMedicine
M1 - 104867
ER -