Restricted antigenic variability of the epitope recognized by the neutralizing gp41 antibody 2F5.

OBJECTIVE: To investigate whether variations of the conserved gp41 amino-acid sequence ELDKWA affect its binding or neutralization by monoclonal antibody (MAb) 2F5. DESIGN AND METHODS: Neutralization assays were performed with primary isolates from different HIV-1 subtypes and the sequences corresponding to the 2F5 epitope region were analysed. Studies of MAb 2F5 peptide reactivity were performed by spot analysis, using peptides immobilized on cellulose. The frequency of emergence of neutralization-resistant virus variants was determined by immune selection experiments in the presence of MAb 2F5. RESULTS: Primary isolates from clades A, B and E were neutralized by MAb 2F5. Neutralization sensitivity correlated with the presence of the LDKW motif. A K-to-N change in the core sequence was identified in a neutralization-resistant patient isolate. Neutralization resistant virus variants that were selected in the presence of MAb 2F5 were found to contain D-to-N, D-to-E, or K-to-N changes within the LDKW sequence. Neither in natural isolates nor in variants obtained under immune selection conditions in the laboratory were changes in the L and W positions observed. Studies of MAb 2F5 binding to variations of the ELDKWA peptide confirmed that the changes at the first and last positions did not significantly reduce binding capacity, whereas amino-acid changes from D to N, D to E, and K to N almost completely abrogated binding of MAb 2F5. CONCLUSION: Sequence analysis of a variety of primary isolates suggests that the major determinant of MAb 2F5 binding corresponds to the amino-acid sequence LDKW. Naturally occurring and in vitro selected neutralization-resistant viruses contained changes in the D and K positions of the ELDKWA motif.

Long-term treatment with growth hormone has no persisting effect on lipoprotein(a) in patients with Turner's syndrome.

Treatment with recombinant human GH (rhGH), alone or in combination with the anabolic steroid oxandrolone (OX), has been recommended for girls with Turner's syndrome to improve final height. Several cardiovascular risk factors have been described in patients with Turner's syndrome, but the effect of therapy with rhGH and OX on lipoprotein(a) [Lp(a)] has not been investigated. Lp(a) serum levels and apolipoprotein(a) phenotypes were determined in 46 girls with Turners syndrome (aged 6-15 yr) during treatment with different combinations of rhGH and OX for 24-36 months (median, 27 months). Lp(a) serum levels showed little variation during 30 months of treatment in all treatment groups. Lp(a) levels showed no significant change in 25 patients receiving only rhGH and in 21 patients receiving rhGH and OX in combination. Treatment effects were independent of apolipoprotein(a) phenotypes and were not influenced by pubertal status. These data indicate that long term administration of rhGH has no significant impact on serum Lp(a) levels in girls with Turner's syndrome.

Detachment of human immunodeficiency virus type 1 from germinal centers by blocking complement receptor type 2.

After the transition from the acute to the chronic phase of human immunodeficiency virus (HIV) infection, complement mediates long-term storage of virions in germinal centers (GC) of lymphoid tissue. The contribution of particular complement receptors (CRs) to virus trapping in GC was studied on tonsillar specimens from HIV-infected individuals. CR2 (CD21) was identified as the main binding site for HIV in GC. Monoclonal antibodies (MAb) blocking the CR2-C3d interaction were shown to detach 62 to 77% of HIV type 1 from tonsillar cells of an individual in the presymptomatic stage. Although they did so at a lower efficiency, these antibodies were able to remove HIV from tonsillar cells of patients under highly active antiretroviral therapy, suggesting that the C3d-CR2 interaction remains a primary entrapment mechanism in treated patients as well. In contrast, removal of HIV was not observed with MAb blocking CR1 or CR3. Thus, targeting CR2 may facilitate new approaches toward a reduction of residual virus in GC.