Background
HIV-1 uses either CCR5 (R5 virus) or CXCR4 (X4 virus) as a coreceptor to enter host cells. X4 variants, usually seen in the late stage of infection, are associated with more rapid disease progression. However, the triggering event that allows the evolution of X4 variants and the dynamics of X4 and R5 variants following the emergence of X4 variants are unclear.
Methods
We identified 21 women with HIV in the Women’s Interagency HIV Study (WIHS) whose: 1) CD4 T+ cell counts declined from >600 to <100 cells/µl in the absent of effective antiviral therapy while in the study, and 2) plasma samples were available during the period of CD4+ T cell decline with HIV-1 RNA quantification. Multiplexed Primer ID NGS targeted HIV-1 gag, pol and env (V1/V3) of longitudinal specimens collected every 6 months. X4 variants were inferred using the Geno2Pheno coreceptor algorithm; X4 lineages were defined as having a false positive rate below 2% and comprising at least 0.3% of the intra-host viral population.
Results
A median of 4 years follow-up were studied for each participant. X4 variants were identified in 16 participants, with a median CD4+ T cell level of 620 cells/µL at the time of detection. At the time point when X4 first emerged, these variants constituted a median of 11% of the intra-host population. X4 variants co-existed with the R5 variants in longitudinal follow-up. At the final time point, the X4 population made up a median of 19% of the intra-host quasispecies. The emergence of X4 variants accelerated disease progression, evidenced by an increased CD4+ T cell decline rate of 206 cells/µl/year (95% CI: 31 to 382, p=0.025) following their emergence. The X4 Env V3 sequences were linked with specific Env V1/V2 lineages, suggesting genetic compartmentalization of X4 variants. In some participants, multiple X4 lineages with distinct V3 sequences were identified at the same time point, suggesting diverse origins of X4 variants. X4 and R5 variants continued to evolve over time. The emergence of X4 did not increase the viral diversity in Env V1/V3.
Conclusions
X4 variants can emerge as minor variants early during the course of HIV-1 infection. X4 viruses co-exist with CCR5-using viruses, suggesting that the evolution of X4 variants is not driven by the lack of CCR5+ CD4+ T cells. We propose that the emergence of X4 viruses serves as a biomarker for a state of virus-specific immunodeficiency, allowing the virus to proliferate in inactivated CXCR4+ CD4+ T cells, leading to a more rapid loss of CD4.
Table or Figure
