CCR5 as a Coreceptor for Human Immunodeficiency Virus and Simian Immunodeficiency Viruses: A Prototypic Love-Hate Affair

Abstract

CCR5, a chemokine receptor central for orchestrating lymphocyte/cell migration to the sites of inflammation and to the immunosurveillance, is involved in the pathogenesis of a wide spectrum of health conditions, including inflammatory diseases, viral infections, cancers and autoimmune diseases. CCR5 is also the primary coreceptor for the human immunodeficiency viruses (HIVs), supporting its entry into CD4⁺ T lymphocytes upon transmission and in the early stages of infection in humans. A natural loss-of-function mutation CCR5-Δ32, preventing the mutated protein expression on the cell surface, renders homozygous carriers of the null allele resistant to HIV-1 infection. This phenomenon was leveraged in the development of therapies and cure strategies for AIDS. Meanwhile, over 40 African nonhuman primate species are long-term hosts of simian immunodeficiency virus (SIV), an ancestral family of viruses that give rise to the pandemic CCR5 (R5)-tropic HIV-1. Many natural hosts typically do not progress to immunodeficiency upon the SIV infection. They have developed various strategies to minimize the SIV-related pathogenesis and disease progression, including an array of mechanisms employing modulation of the CCR5 receptor activity: (i) deletion mutations abrogating the CCR5 surface expression and conferring resistance to infection in null homozygotes; (ii) downregulation of CCR5 expression on CD4⁺ T cells, particularly memory cells and cells at the mucosal sites, preventing SIV from infecting and killing cells important for the maintenance of immune homeostasis, (iii) delayed onset of CCR5 expression on the CD4⁺ T cells during ontogenetic development that protects the offspring from vertical transmission of the virus. These host adaptations, aimed at lowering the availability of target CCR5⁺ CD4⁺ T cells through CCR5 downregulation, were countered by SIV, which evolved to alter the entry coreceptor usage toward infecting different CD4⁺ T-cell subpopulations that support viral replication yet without disruption of host immune homeostasis. These natural strategies against SIV/HIV-1 infection, involving control of CCR5 function, inspired therapeutic approaches against HIV-1 disease, employing CCR5 coreceptor blocking as well as gene editing and silencing of CCR5. Given the pleiotropic role of CCR5 in health beyond immune disease, the precision as well as costs and benefits of such interventions needs to be carefully considered.

Keywords: African green monkey; CCR5; delta 32; human immunodeficiency virus; red-capped mangabey; simian immunodeficiency virus; sooty mangabey; virus transmission.

Figure 1

From natural control of CCR5 activity to therapeutic approaches against HIV disease. CCR5 null alleles, preventing CCR5-mediated virus entry, naturally emerged and raised to high frequency in different primate species most likely as a result of host adaptation to lethal pathogens (unknown ancient pathogen in humans and SIV in natural hosts) (top right). CCR5 downregulation of CCR5 on CD4+ T-cells may be an adaptive feature of natural hosts protecting against the vertical transmission of the virus (via breast feeding), and it may also represent an evolutionary adaptation to spare essential CD4+ T-cell subsets from killing by the virus (bottom right). Examples of approaches for therapeutic disruption of CCR5 expression include natural CCR5 gene knockouts (resulting in functional cure), programmable nucleases, and gene silencing (top left) and approaches to blocking the virus fusion with cell membrane via chemical CCR5 receptor antagonists or antibodies (bottom left). Cryo-EM structure of the chemokine receptor CCR5 (green) in complex with RANTES and guanine nucleotide-binding protein Gi subunits alpha-1 (red), beta-1 (blue), and gamma-2 (magenta) was acquired from https://www.rcsb.org/3d-view/7F1R/1 wwPDB: Worldwide Protein Data Bank (13, 31, 32).

Figure 2

Host-pathogen co-adaptations in a natural (left) and non-natural host (right). On the left, a putative origin of a unique among SIVs CCR2-tropic SIVrcm infecting red-capped mangabey RCM: A high frequency of CCR5-Δ24 mutation, disrupting CCR5 function and protecting from infection with CCR5-tropic SIV, led to the virus adaptation via changing the usage of CCR5 to CCR2b for cell entry (60). On the right, SIVrcm adaptation of coreceptor usage to a new host: experimental SIVrcm infection of pigtailed macaque, a natural host, showed a CCR2 usage in early infection and expansion of coreceptor usage to CCR4 demonstrating that lentiviral adaptation may occur rapidly through strain selection (170).

Figure 3

Change of coreceptor tropism (loss of CXCR6 usage) in the SIVcpz/HIV-1 lineage may contribute to increased use of CCR5 as an entry coreceptor, more widespread infection of target cells and enhanced pathogenicity of SIVcpz/HIV-1 in chimpanzee and human, respectively (187).