Patterns of Chemokine Receptor Fusion Cofactor Utilization by Human Immunodeficiency Virus Type 1 Variants from the Lungs and Blood

Abstract

Human immunodeficiency virus type 1 (HIV-1) infection is highly compartmentalized, with distinct viral genotypes being found in the lungs, brain, and other organs compared with blood. CCR5 and CXCR4 are the principal HIV-1 coreceptors, and a number of other molecules support entry in vitro but their roles in vivo are uncertain. To address the relationship between tissue compartmentalization and the selective use of entry coreceptors, we generated functionalenv clones from primary isolates derived from the lungs and blood of three infected individuals and analyzed their use of the principal, secondary, orphan, and virus-encoded coreceptors for fusion. All Env proteins from lung viruses used CCR5 but not CXCR4, while those from blood viruses used CCR5 or CXCR4 or both. The orphan receptor APJ was widely used for fusion by Env proteins from both blood and lung viruses, but none used the cytomegalovirus-encoded receptor US28. Fusion mediated by the secondary coreceptors CCR2b, CCR3, CCR8, and CX3CR1 and orphan receptors GPR1, GPR15, and STRL33 was variable and heterogeneous, with relatively broad utilization byenv clones from isolates of one subject but limited use byenv clones from the other two subjects. However, there was no clear distinction between blood and lung viruses in secondary or orphan coreceptor fusion patterns. In contrast to fusion, none of the secondary or orphan receptors enabled efficient productive infection. These results confirm, at the level of cofactor utilization, previous observations that HIV-1 populations in the lungs and blood are biologically distinct and demonstrate diversity within lung-derived as well as blood-derived quasispecies. However, the heterogeneity in coreceptor utilization among clones from each isolate and the lack of clear distinction between lung- and blood-derived Env proteins argue against selective coreceptor utilization as a major determinant of compartmentalization.

HIV-1 coreceptor preference is distinct from target cell tropism: a dual-parameter nomenclature to define viral phenotypes

“…Coreceptor-dependent, Env-mediated fusion is assessed on the basis of transactivation of a reporter gene due to cell content mixing [11,12], although Env overexpression in effector cells may lead to differences from Env expressed in the context of virions. In particular, cell-cell fusion assays may overestimate coreceptor utilization when compared with infection, for example, many minor coreceptors that support HIV-1 cell-cell fusion assays are less active or even inactive in the context of virus infection [63,64].…”

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“…It is mapped at 2q33.3 and encodes for a G proteincoupled receptor for the inflammation-associated leukocyte chemoattractant chemerin/RARRES2 [retinoic acid receptor responder (tazarotene induced) 2] considered as an adipokine in children 106 , as well as for a putative membrane-bound G protein, associated in the activation of cAMP synthesis 107 . GPR1 protein"s role as a coreceptor for HIV-1 is supported by the literature [108][109][110] . The GPR1 G protein-coupled receptor suggests an association with respiratory distress syndrome (RDS).…”

The Complexity of HIV Persistence and Pathogenesis in the Lung Under Antiretroviral Therapy: Challenges Beyond AIDS

“…Because both NSI and SI variants were detected in different tissues, the existence of tissue reservoirs apart from the brain was discounted, and the presence of HIV in nonlymphoid tissues was seen as a late-stage event secondary to lymphocyte infiltration (168). By using functional env clones from primary isolates, Singh's group (151) examined the HIV co-receptor utilization patterns in the lung and showed that the lung isolates used CCR5 as exclusive co-receptor, while the blood isolates may use either CCR5 or CXCR4. Furthermore, lung and blood isolates were undistinguishable regarding the use of secondary co-receptors, including CCR2b, CCR3, CCR8, and CX3CR1 and orphan receptors GPR1, GPR15, and STRL33, suggesting that co-receptor utilization does not determine HIV compartmentalization in the lung, despite the biological differences between HIV quasispecies in the blood and the lung.…”