biostudies-literatureSalimi HU.S. National Institutes of Health/NIAIDIranian Ministry of Health and Medical EducationNIAID NIH HHSSir Zelman Cowen Fellowship Fund, Burnet InstituteNHMRCSir Zelman Cowen Senior Research FellowAustralian NHMRC Early Career Research FellowshipAustralian NHMRC Level 2 Biomedical Career Development Award113-26https://www.ebi.ac.uk/biostudies/studies/S-EPMC3525831biostudies-literatureUnknown93(1)BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. SecondJournal of leukocyte biologyMacrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5.PMC3525831R21 AI092218#603708#1006534Chikere KLee BGray LREllett ARamsland PAChurchill MJSterjovski JWesselingh SLSalimi HRoche MGorry PRWebb NfalseMacrophage-tropic HIV-1 variants from brain demonstrate alterations in the way gp120 engages both CD4 and CCR5.BR-derived HIV-1 strains have an exceptional ability to enter macrophages via mechanisms involving their gp120 Env that remain incompletely understood. Here, we used cell-based affinity-profiling methods and mathematical modeling to generate quantitative VERSA metrics that simultaneously measure Env-CD4 and Env-CCR5 interactions. These metrics were analyzed to distinguish the phenotypes of M-tropic and non-M-tropic CCR5-using HIV-1 variants derived from autopsy BRs and LNs, respectively. We show that highly M-tropic Env variants derived from brain can be defined by two distinct and simultaneously occurring phenotypes. First, BR-derived Envs demonstrated an enhanced ability to interact with CD4 compared with LN-derived Envs, permitting entry into cells expressing scant levels of CD4. Second2013-01-01T00:00:00Z2013 Jan2026-05-05T16:59:23.688Z2026-04-07T21:52:04.411ZS-EPMC35258312307724610.1189/jlb.0612308