Loss of CXCR6 coreceptor usage characterizes pathogenic lentiviruses

Abstract

Pandemic HIV-1 originated from the cross-species transmission of SIVcpz, which infects chimpanzees, while SIVcpz itself emerged following the cross-species transmission and recombination of monkey SIVs, with env contributed by the SIVgsn/mus/mon lineage that infects greater spot-nosed, mustached and mona monkeys. SIVcpz and HIV-1 are pathogenic in their respective hosts, while the phenotype of their SIVgsn/mus/mon ancestors is unknown. However, two well-studied SIV infected natural hosts, sooty mangabeys (SMs) and African green monkeys (AGMs), typically remain healthy despite high viral loads; these species express low levels of the canonical coreceptor CCR5, and recent work shows that CXCR6 is a major coreceptor for SIV in these hosts. It is not known what coreceptors were used by the precursors of SIVcpz, whether coreceptor use changed during emergence of the SIVcpz/HIV-1 lineage, and what T cell subsets express CXCR6 in natural hosts. Using species-matched coreceptors and CD4, we show here that SIVcpz uses only CCR5 for entry and, like HIV-1, cannot use CXCR6. In contrast, SIVmus efficiently uses both CXCR6 and CCR5. Coreceptor selectivity was determined by Env, with CXCR6 use abrogated by Pro326 in the V3 crown, which is absent in monkey SIVs but highly conserved in SIVcpz/HIV-1. To characterize which cells express CXCR6, we generated a novel antibody that recognizes CXCR6 of multiple primate species. Testing lymphocytes from SM, the best-studied natural host, we found that CXCR6 is restricted to CD4+ effector memory cells, and is expressed by a sub-population distinct from those expressing CCR5. Thus, efficient CXCR6 use, previously identified in SM and AGM infection, also characterizes a member of the SIV lineage that gave rise to SIVcpz/HIV-1. Loss of CXCR6 usage by SIVcpz may have altered its cell tropism, shifting virus from CXCR6-expressing cells that may support replication without disrupting immune function or homeostasis, towards CCR5-expressing cells with pathogenic consequences.

Simian Immunodeficiency Virus Persistence in Cellular and Anatomic Reservoirs in Antiretroviral Therapy-Suppressed Infant Rhesus Macaques

“…HIV/SIV coreceptor CCR5 expression on the surfaces of naive CD4 ϩ T cells is very low, and viral entry could involve alternative coreceptors, such as CXCR4 in humans or CXCR6 and GPR15 in monkeys (39,40). However, both SIV mac251 , used in this study, and SIV mac239 have been shown to exclusively use CCR5 for entry into rhesus macaque CD4 ϩ T cells (41,42). The lymphoid tissue microenvironment may also have an important role in HIV infection of naive T cells, with increased susceptibility to infection in tonsil lymphoid tissue compared to purified CD4 ϩ T cells alone (43,44).…”

Epigenetic silencing of CD4 expression in nonpathogenic SIV infection in African green monkeys

“…We reasoned that genes reported to play putative roles in disease nonprogression of natural hosts would be present in this set of genes. Indeed, CXCR6, the preferred coreceptor of SIV agm that is thought to divert replication from more stem-like CD4 + CCR5 + central memory cells ( 20 , 21 ), was uniquely upregulated in CFSE – CD4 – cells of AGMs and patas monkeys and yet not in rhesus CFSE – CD4 + cells ( Figure 1D ). Importantly, CD4 was one of the most significant DEGs that was unique to CFSE – CD4 + cells ( Figure 1D ), as African green and patas (but not rhesus) CD4 + T cells exhibited significant loss of CD4 transcription in CFSE – CD4 – cells ( Figure 1E ).…”

Le réservoir viral dans l’infection par le VIH-2, modèle d’une infection rétrovirale atténuée

“…Les monocytes ainsi que des sous-populations de lymphocytes T CD4 + au reposnaïfs TN (T naive), à mémoire centrale TCM, à mémoire transitionnelle TTM, et à mémoire effectrice TEM (T effector memory) (Figure 2), et nous avons pu confirmer cette différence en analysant l'expression de la protéine CXCR6 par cytométrie en flux ( Figure 3A). Comme il a été récemment montré que l'utilisation du CXCR6 caractérise l'infection par les lentivirus non pathogènes [9] et qu'elle est abrogée par la présence d'une proline en position 326 de la boucle V3 de la glycoprotéine d'enveloppe gp105, nous avons examiné les 259 séquences de gp105 du VIH-2 dont nous disposions pour la cohorte ANRS-VIH-2, mais aucune de ces séquences ne comportait une proline à cette position. L'analyse transcriptomique a également montré que le gène TRIM5a était plus exprimé dans les TCM que dans les TTM (Figure 2), mais l'analyse de l'expression de la protéine par cytométrie en flux n'a pas permis de confirmer cette différence ( Figure 3B).…”

“…De plus, le VIH-2, qui utilise les mêmes co-récepteurs CCR5 (C-C chemokine receptor 5) et CXCR4 (c-x-c chemokine receptor 4) que le VIH-1 pour infecter les cellules [6], semble utiliser un plus large spectre de co-récepteurs alternatifs (CCR1 à CCR8, CXCR6, GPR15 [G protein-coupled receptor 15], GPR1, APJ [putative receptor protein related to AT1], CX3CR1 (V28), CXCR5 et RDC1/ CXCR7) in vitro [7]. CXCR6 pourrait être un des co-récepteurs alternatifs majeur du VIH-2 car il serait préférentiellement utilisé chez les patients avirémiques infectés par le VIH-2 [8] ainsi que dans les infections par les lentivirus simiens non pathogènes [9]. Comme pour le VIH-1, l'infection par le VIH-2 semble aboutir à la constitution d'un réservoir de cellules infectées.…”