Higher CCR5 density on CD4+ T-cells in mothers and infants is associated with increased risk of in-utero HIV-1 transmission

Objective: CCR5-tropic viruses are preferentially transmitted during perinatal HIV-1 infection. CCR5 density on CD4(+) T-cells likely impacts susceptibility to HIV-1 infection. Design: Fifty-two mother-infant dyads were enrolled. All mothers were living with HIV-1, 27 of the infants acquired HIV-1 in utero and 25 infants remained uninfected. Methods: CCR5 density, together with frequencies of CD4(+) and CD8(+) T-cells expressing immune activation (CCR5, ICOS and HLA-DR) and immune checkpoint (TIGIT and PD-1) markers, were measured in whole blood from the dyads close to delivery. Results: Compared with mothers who did not transmit, mothers who transmitted HIV-1 had less exposure to ART during pregnancy (P = 0.015) and higher plasma viral load close to delivery (P = 0.0005). These mothers, additionally, had higher CCR5 density on CD4(+) and CD8(+) T-cells and higher frequencies of CCR5, ICOS and TIGIT-expressing CD8(+) T-cells. Similarly, compared with infants without HIV-1, infants with HIV-1 had higher CCR5 density on CD4(+) and CD8(+) T-cells and higher frequencies of CCR5, TIGIT, and PD-1-expressing CD4(+) and CD8(+) T-cells as well as higher frequencies of HLA-DR-expressing CD8(+) T-cells. CCR5 density on maternal CD4(+) T-cells remained significantly associated with transmission after adjusting for maternal viral load and CD4(+) T cell counts. Mother-infant dyads with shared high CCR5 density phenotypes had the highest risk of transmission/acquisition of infection compared with dyads with shared low-CCR5 density phenotypes. Conclusion: This study provides strong evidence of a protective role for a combined mother-infant low CD4+ T-cell CCR5 density phenotype in in-utero transmission/acquisition of HIV-1.