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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.

Peters PJ, Duenas-Decamp MJ, Sullivan WM, Brown R, Ankghuambom C, Luzuriaga K, Robinson J, Burton DR, Bell J, Simmonds P, Ball J, Clapham PR - Retrovirology (2008)

Bottom Line: These observations were highly significant and are consistent with an increased affinity of envelope for CD4 for macrophage-tropic envelopes.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.Such variation has important implications for therapy using viral entry inhibitors and for the design of envelope antigens for vaccines.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for AIDS Research, Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, 373 Plantation Street, University of Massachusetts Medical School, Worcester, MA 01605, USA. Paul.Peters@umassmed.edu

ABSTRACT

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.

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Sensitivity of HIV-1 R5 envelopes to inhibition by Q4120 and PRO 542 correlates with macrophage-tropism. HIV-1 R5 macrophage-tropism correlated with an increased sensitivity to PRO 542 but decreased sensitivity to Q4120 and BMS378806. HIV-1 R5 macrophage-tropism also correlated with sensitivity to 2G12 but not with b12, TAK779, SCH350581 or T20 (see complete list of p values in Table 2).
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Figure 6: Sensitivity of HIV-1 R5 envelopes to inhibition by Q4120 and PRO 542 correlates with macrophage-tropism. HIV-1 R5 macrophage-tropism correlated with an increased sensitivity to PRO 542 but decreased sensitivity to Q4120 and BMS378806. HIV-1 R5 macrophage-tropism also correlated with sensitivity to 2G12 but not with b12, TAK779, SCH350581 or T20 (see complete list of p values in Table 2).

Mentions: Table 2 and Figure 6 show that R5 macrophage-tropism correlates with sensitivity to inhibitors that interfere with gp120:CD4 interactions. There was also a significant correlation between increased macrophage-tropism and with decreased sensitivity to 2G12 neutralization. No overall correlation was noted between macrophage-tropism and sensitivity to the gp41 mabs or T20. In summary, R5 macrophage-tropism correlated with sensitivity to reagents that interfere with gp120:CD4 binding but not with inhibitors that prevent gp120, CCR5 interactions or gp41 conformational changes.


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.

Peters PJ, Duenas-Decamp MJ, Sullivan WM, Brown R, Ankghuambom C, Luzuriaga K, Robinson J, Burton DR, Bell J, Simmonds P, Ball J, Clapham PR - Retrovirology (2008)

Sensitivity of HIV-1 R5 envelopes to inhibition by Q4120 and PRO 542 correlates with macrophage-tropism. HIV-1 R5 macrophage-tropism correlated with an increased sensitivity to PRO 542 but decreased sensitivity to Q4120 and BMS378806. HIV-1 R5 macrophage-tropism also correlated with sensitivity to 2G12 but not with b12, TAK779, SCH350581 or T20 (see complete list of p values in Table 2).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2268948&req=5

Figure 6: Sensitivity of HIV-1 R5 envelopes to inhibition by Q4120 and PRO 542 correlates with macrophage-tropism. HIV-1 R5 macrophage-tropism correlated with an increased sensitivity to PRO 542 but decreased sensitivity to Q4120 and BMS378806. HIV-1 R5 macrophage-tropism also correlated with sensitivity to 2G12 but not with b12, TAK779, SCH350581 or T20 (see complete list of p values in Table 2).
Mentions: Table 2 and Figure 6 show that R5 macrophage-tropism correlates with sensitivity to inhibitors that interfere with gp120:CD4 interactions. There was also a significant correlation between increased macrophage-tropism and with decreased sensitivity to 2G12 neutralization. No overall correlation was noted between macrophage-tropism and sensitivity to the gp41 mabs or T20. In summary, R5 macrophage-tropism correlated with sensitivity to reagents that interfere with gp120:CD4 binding but not with inhibitors that prevent gp120, CCR5 interactions or gp41 conformational changes.

Bottom Line: These observations were highly significant and are consistent with an increased affinity of envelope for CD4 for macrophage-tropic envelopes.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.Such variation has important implications for therapy using viral entry inhibitors and for the design of envelope antigens for vaccines.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for AIDS Research, Program in Molecular Medicine and Department of Molecular Genetics and Microbiology, 373 Plantation Street, University of Massachusetts Medical School, Worcester, MA 01605, USA. Paul.Peters@umassmed.edu

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus