Summary auto-generated
This 1999 study investigated whether primary HIV-1 isolates can use alternative coreceptors BOB/GPR15 and Bonzo/STRL33 for viral entry and replication. Researchers tested 15 gp160 envelope clones representing HIV-1 subtypes A-F using pseudotyped reporter viruses and cell-based assays. BOB/GPR15 was used by the majority of HIV-1 envelopes (9 of 15), though with low efficiency compared to the major coreceptors CCR5 and CXCR4. Bonzo/STRL33 usage was less common and typically inefficient. Critically, when testing uncloned primary isolates and molecular clones for productive replication, only isolates with X4-tropic or R5X4-tropic tropism replicated efficiently using BOB/GPR15, while no isolates replicated in Bonzo/STRL33-expressing cells. Three primary isolates (92UG021, 93BR020, 92HT596) and two molecular clones showed efficient replication via BOB/GPR15. The study demonstrates that while BOB/GPR15 can mediate HIV-1 entry relatively broadly, productive viral replication through this pathway is limited to specific biological phenotypes, suggesting BOB/GPR15 may play a minor but potentially relevant role in HIV-1 pathogenesis.
Key findings
- BOB/GPR15 serves as a coreceptor for entry of most primary HIV-1 envelopes tested (9 of 15), though with efficiency at least 10-fold lower than major coreceptors CCR5 and CXCR4
- Bonzo/STRL33 is used less frequently and inefficiently by HIV-1, with only 5 of 15 envelopes showing any detectable entry activity
- Only 3 primary HIV-1 isolates and 2 molecular clones replicate efficiently in BOB/GPR15-expressing cells, all showing X4-tropic or R5X4-tropic phenotypes
- No HIV-1 variant tested achieved significant replication in Bonzo/STRL33-expressing cells, limiting its relevance for viral replication
- BOB/GPR15-mediated HIV-1 infection appears dependent on high coreceptor expression levels and is inefficient despite measurable entry, suggesting limited but potentially meaningful role in certain infection contexts
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Abstract
Primary isolates of human and simian immunodeficiency viruses (HIV and SIV) use the chemokine receptor CCR5, in association with CD4, as coreceptor. During AIDS progression, HIV-1 and HIV-2 often adapt to use additional cofactors, particularly CXCR4. In contrast, SIV isolates do not use CXCR4, but other coreceptors such as BOB/GPR15 and Bonzo/STRL33. Only limited information is currently available on usage of BOB/GPR15 and Bonzo/STRL33 by HIV-1. Therefore, we investigated a panel of gp160 clones from 15 primary isolates, representing 5 different subtypes, for utilization of these cofactors. The majority of HIV-1 envelopes mediated entry into BOB/GPR15-expressing cells, albeit often with low efficiency. Usage of Bonzo/STRL33 was less common and usually inefficient. To investigate if HIV-1 entry via these orphan receptors is sufficient to allow virus replication, 15 uncloned primary HIV-1 isolates and 7 molecular clones were used to infect target cells expressing CD4 and Bonzo/STRL33 or BOB/GPR15. Three primary isolates and two molecular clones replicated efficiently in cells expressing BOB/GPR15. Two of these isolates were X4-tropic, two were R5X4-tropic and one was R5-tropic. In contrast, none of the HIV-1 variants showed significant levels of replication in Bonzo/STRL33-expressing cells. Our data show that some HIV-1 isolates of different genetic subtype and of different biological phenotype use BOB/GPR15 for productive infection and suggest that this cofactor may play a role in HIV-1 pathogenesis and transmission.