title: Increased sensitivity to broadly neutralizing antibodies of end-stage disease R5 HIV-1 correlates with evolution in Env glycosylation and charge.
abstract: BACKGROUND
  Induction of broadly neutralizing antibodies, such as the monoclonal antibodies IgGb12, 2F5 and 2G12, is the objective of most antibody-based HIV-1 vaccine undertakings. However, despite the relative conserved nature of epitopes targeted by these antibodies, mechanisms underlying the sensitivity of circulating HIV-1 variants to broadly neutralizing antibodies are not fully understood. Here we have studied sensitivity to broadly neutralizing antibodies of HIV-1 variants that emerge during disease progression in relation to molecular alterations in the viral envelope glycoproteins (Env), using a panel of primary R5 HIV-1 isolates sequentially obtained before and after AIDS onset.
  
  
  RESULTS
  HIV-1 R5 isolates obtained at end-stage disease, after AIDS onset, were found to be more sensitive to neutralization by TriMab, an equimolar mix of the IgGb12, 2F5 and 2G12 antibodies, than R5 isolates from the chronic phase. The increased sensitivity correlated with low CD4(+) T cell count at time of virus isolation and augmented viral infectivity. Subsequent sequence analysis of multiple env clones derived from the R5 HIV-1 isolates revealed that, concomitant with increased TriMab neutralization sensitivity, end-stage R5 variants displayed envelope glycoproteins (Envs) with reduced numbers of potential N-linked glycosylation sites (PNGS), in addition to increased positive surface charge. These molecular changes in Env also correlated to sensitivity to neutralization by the individual 2G12 monoclonal antibody (mAb). Furthermore, results from molecular modeling suggested that the PNGS lost at end-stage disease locate in the proximity to the 2G12 epitope.
  
  
  CONCLUSIONS
  Our study suggests that R5 HIV-1 variants with increased sensitivity to broadly neutralizing antibodies, including the 2G12 mAb, may emerge in an opportunistic manner during severe immunodeficiency as a consequence of adaptive molecular Env changes, including loss of glycosylation and gain of positive charge.
authors.affiliation: Department of Laboratory Medicine, Lund University, Lund, Sweden.
authors.forename: Marie
authors.initials: M
authors.lastname: Borggren
authors.forename: Johanna
authors.initials: J
authors.lastname: Repits
authors.forename: Jasminka
authors.initials: J
authors.lastname: Sterjovski
authors.forename: Hannes
authors.initials: H
authors.lastname: Uchtenhagen
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Churchill
authors.forename: Anders
authors.initials: A
authors.lastname: Karlsson
authors.forename: Jan
authors.initials: J
authors.lastname: Albert
authors.forename: Adnane
authors.initials: A
authors.lastname: Achour
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Eva Maria
authors.initials: EM
authors.lastname: Fenyö
authors.forename: Marianne
authors.initials: M
authors.lastname: Jansson
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D015686:Gene Products, env / Q000378:metabolism*; D006031:Glycosylation; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D008969:Molecular Sequence Data
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015686:Gene Products, env