Identifying CCR5 coreceptor populations permissive for HIV-1 entry and productive infection: implications for in vivo studies

Abstract

Background The chemokine receptor CCR5 is the major coreceptor for HIV-1 cell entry. We previously observed that not all CCR5 mAbs reduce HIV-1 infection, suggesting that only some CCR5 populations are permissive for HIV-1 entry. This study aims to better understand the relevant conformational states of the cellular coreceptor, CCR5, involved in HIV entry. We hypothesized that CCR5 assumes multiple configurations during normal cycling on the plasma membrane, but only particular forms facilitate HIV-1 infection. Methods To this end, we quantified different CCR5 populations using six CCR5 monoclonal antibodies (mAbs) with different epitope specificities and visualized them with super-resolution microscopy. We quantified each surface CCR5 population before and after HIV-1 infection. Results Based on CCR5 conformational changes, down-modulation, and trafficking rates (internalization and recycling kinetics), we were able to distinguish among heterogeneous CCR5 populations and thus which populations might best be targeted to inhibit HIV-1 entry. We assume that a decreased surface presence of a particular CCR5 subpopulation following infection means that it has been internalized due to HIV-1 entry, and that it therefore represents a highly relevant target for future antiviral therapy strategies. Strikingly, this was most true for antibody CTC8, which targets the N-terminal region of CCR5 and blocks viral entry more efficiently than it blocks chemokine binding. Conclusions Defining the virus-host interactions responsible for HIV-1 transmission, including specific coreceptor populations capable of establishing de novo infections, is essential for the development of an HIV-1 vaccine. This study hopefully will facilitate further development of inhibitors to block CCR5 usage by HIV-1, as well as inform future HIV-1 vaccine design.

Akkermansia muciniphila and herbal medicine in immune-related diseases: current evidence and future perspectives

“…The CC chemokine receptor 5 is an attractive target for HIV as it is expressed at high levels in intestinal CD4 T cells, which are severely depleted during infection (Brenchley and Douek, 2008;Weichseldorfer et al, 2022). HIV infection disrupts the intestinal barrier, leading to translocation of microbial products.…”

A Predictive Model for Identifying the Most Effective Anti-CCR5 Monoclonal Antibody

“…Monoclonal antibodies (mAbs) that act as antagonists of CCR5 have been increasingly examined [7] and have led to many potential therapeutic solutions [3,[8][9][10][11][12][13][14][15][16][17][18][19][20]. However, currently, there is information lacking about the structural interaction between mAbs and CCR5 [21].…”

Single-molecule and super-resolved imaging deciphers membrane behavior of onco-immunogenic CCR5

“…Previous studies investigating the antigenic behavior of CCR5 suggest the existence of multiple conformational subpopulations of CCR5, an observation that is derived from the characteristic recognition of structurally distinct ligands by varying proportions of cell surface CCR5. 16 , 17 , 18 , 19 Further, CCR5 has been shown to exist in both homodimeric and heterodimeric states, with the homodimerization of CCR5 being shown to take place in the ER before reaching the cell surface, 20 any downstream clustering would therefore be expected to carry a periodicity in the apparent stoichiometry of two molecules. 21 Considering that the various purported conformational and oligomeric states of CCR5 exhibit downstream effects on the receptor chemotactic functionality, 17 , 22 the nature of this heterogeneity requires further investigation.…”