Low CCR5 expression protects HIV-specific CD4+ T cells of elite controllers from viral entry

Abstract

HIV elite controllers maintain a population of CD4 + T cells endowed with high avidity for Gag antigens and potent effector functions. How these HIV-specific cells avoid infection and depletion upon encounter with the virus remains incompletely understood. Ex vivo characterization of single Gag-specific CD4 + T cells reveals an advanced Th1 differentiation pattern in controllers, except for the CCR5 marker, which is downregulated compared to specific cells of treated patients. Accordingly, controller specific CD4 + T cells show decreased susceptibility to CCR5-dependent HIV entry. Two controllers carried biallelic mutations impairing CCR5 surface expression, indicating that in rare cases CCR5 downregulation can have a direct genetic cause. Increased expression of β-chemokine ligands upon high-avidity antigen/TCR interactions contributes to autocrine CCR5 downregulation in controllers without CCR5 mutations. These findings suggest that genetic and functional regulation of the primary HIV coreceptor CCR5 play a key role in promoting natural HIV control.

MiRNA-103 downmodulates CCR5 expression reducing human immunodeficiency virus type-1 entry and impacting latency establishment in CD4+ T cells

“…Several studies have shown that PBMCs from ECs have a miRNA repertoire that is distinct from that of HIV-1 ART-naïve progressors, and such a difference may in part explain the control of viral infection in ECs ( Witwer et al., 2012 ; Reynoso et al., 2014 ; Ayala-Suárez et al., 2020 ). In this context, we assessed the levels of miRNA-103 and CCR5 mRNA in CD4 + T cells from ECs and ART-naïve progressors and found that CCR5 mRNA in CD4 + T cells obtained from ECs was significantly decreased when compared to that in CD4 + T cells from ART-naïve progressors, in line with recently published results ( Claireaux et al., 2022 ; Gonzalo-Gil et al., 2019 ; Meijerink et al., 2014 ). Thus, in addition to displaying specific immune signatures ( Krishnan et al., 2014 ; Nguyen et al., 2019 ), ECs could also control HIV-1 infection by limiting CCR5 expression levels, particularly in HIV-1-specific CD4 + T cells, via multiple mechanisms, a characteristic that results in decreased susceptibility to viral infection and depletion ( Claireaux et al., 2022 ).…”

“…Indeed, so far, cases of sterilizing cure have been achieved in patients that received allogeneic hematopoietic stem cell transplantation (HSCT) from donors homozygous for the CCR5-Δ32 deletion, which impairs surface expression of the CCR5 receptor and therefore confers resistance to infection ( Gupta et al., 2019 , 2020 ; Hütter et al., 2009 ). Furthermore, highly functional HIV-1-specific CD4 + T cells of ECs were found less susceptible to HIV-1 entry owing to a negative regulation of the CCR5 co-receptor, a characteristic that appears to protect these cells from depletion and promote HIV-1 control ( Claireaux et al., 2022 ; Gonzalo-Gil et al., 2019 ; Meijerink et al., 2014 ). Thus, understanding how CCR5 is regulated in CD4 + T cells is essential for the development of CCR5-targeted therapies aimed at reducing the establishment of latent viral reservoirs and achieving a functional HIV-1 cure.…”

Long-term antiretroviral therapy initiated in acute HIV infection prevents residual dysfunction of HIV-specific CD8+ T cells

“…Spontaneous controllers do not experience sustained levels of viremia and have protective genetic backgrounds such as CCR5Δ32 or protective HLA alleles that are different from most people living with HIV. 44 , 45 , 46 , 47 Therefore, HIV-specific CD8 + T cells in spontaneous controllers might not be the best comparator to determine the level of functionality of HIV-specific CD8 + T cells in people on ART. Comparing the functionality of HIV-specific CD8 + T cells in people who initiated ART during AHI or CHI allows to compare individual with similar genetic backgrounds but having experienced different HIV antigen burden prior to ART.…”

Novel small synthetic HIV-1 V3 crown variants: CCR5 targeting ligands

“…Several studies showed that the host factors and effective immunologic response plays crucial role in controlling the infection ( 91 , 92 ) . A recent study has shown that HIV-specific CD4+ T cells of controllers express low levels of CCR5, which inhibits the entry of HIV-1 ( 93 ) . Thus, the CCR5 represents a target with multifaceted effects in the case of HIV-1 pathogenesis and disease progression.…”