Center for AIDS Research; Program in Molecular Medicine; Department of Molecular Genetics and Microbiology; Department of Pediatrics
Adult; Antibodies, Monoclonal; Brain; Cell Line; HIV Antibodies; HIV Envelope Protein gp120; HIV Fusion Inhibitors; HIV Infections; HIV-1; Humans; Infant; Inhibitory Concentration 50; Lymph Nodes; Macrophages; Neutralization Tests; Virus Internalization
Life Sciences | Medicine and Health Sciences
BACKGROUND: HIV-1 R5 viruses cause most of the AIDS cases worldwide and are preferentially transmitted compared to CXCR4-using viruses. Furthermore, R5 viruses vary extensively in capacity to infect macrophages and highly macrophage-tropic variants are frequently identified in the brains of patients with dementia. Here, we investigated the sensitivity of R5 envelopes to a range of inhibitors and antibodies that block HIV entry. We studied a large panel of R5 envelopes, derived by PCR amplification without culture from brain, lymph node, blood and semen. These R5 envelopes conferred a wide range of macrophage tropism and included highly macrophage-tropic variants from brain and non-macrophage-tropic variants from lymph node. RESULTS: R5 macrophage-tropism correlated with sensitivity to inhibition by reagents that inhibited gp120:CD4 interactions. Thus, increasing macrophage-tropism was associated with increased sensitivity to soluble CD4 and to IgG-CD4 (PRO 542), but with increased resistance to the anti-CD4 monoclonal antibody (mab), Q4120. These observations were highly significant and are consistent with an increased affinity of envelope for CD4 for macrophage-tropic envelopes. No overall correlations were noted between R5 macrophage-tropism and sensitivity to CCR5 antagonists or to gp41 specific reagents. Intriguingly, there was a relationship between increasing macrophage-tropism and increased sensitivity to the CD4 binding site mab, b12, but decreased sensitivity to 2G12, a mab that binds a glycan complex on gp120. CONCLUSION: Variation in R5 macrophage-tropism is caused by envelope variation that predominantly influences sensitivity to reagents that block gp120:CD4 interactions. Such variation has important implications for therapy using viral entry inhibitors and for the design of envelope antigens for vaccines.
DOI of Published Version
Retrovirology. 2008 Jan 18;5:5. Link to article on publisher's site
Peters, Paul J.; Duenas-Decamp, Maria J.; Sullivan, W. Matthew; Brown, Richard J. P.; Ankghuambom, Chiambah; Luzuriaga, Katherine; Robinson, James E.; Burton, Dennis R.; Bell, Jeanne E.; Simmonds, Peter; Ball, K. Jonathan; and Clapham, Paul R., "Variation in HIV-1 R5 macrophage-tropism correlates with sensitivity to reagents that block envelope: CD4 interactions but not with sensitivity to other entry inhibitors" (2008). Open Access Articles. 2012.