Coexistence of potent HIV-1 broadly neutralizing antibodies and antibody-sensitive viruses in a viremic controller

Abstract

Some HIV-1–infected patients develop broad and potent HIV-1 neutralizing antibodies (bNAbs) that when passively transferred to mice or macaques can treat or prevent infection. However, bNAbs typically fail to neutralize coexisting autologous viruses due to antibody-mediated selection against sensitive viral strains. We describe an HIV-1 controller expressing HLA-B57*01 and HLA-B27*05 who maintained low viral loads for 30 years after infection and developed broad and potent serologic activity against HIV-1. Neutralization was attributed to three different bNAbs targeting non-overlapping sites on the HIV-1 envelope trimer (Env). One of the three, BG18, an antibody directed against the glycan-V3 portion of Env, is the most potent member of this class reported to date and, as revealed by crystallography and electron microscopy, recognizes HIV-1 Env in a manner that is distinct from other bNAbs in this class. Single-genome sequencing of HIV-1 from serum samples obtained over a period of 9 years showed a diverse group of circulating viruses, 88.5%(31 of 35) of which remained sensitive to at least one of the temporally coincident autologous bNAbs and the individual’s serum. Thus, bNAb-sensitive strains of HIV-1 coexist with potent neutralizing antibodies that target the virus and may contribute to control in this individual. When administered as a mix, the three bNAbs controlled viremia in HIV-1YU2–infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection.

Asymmetric recognition of HIV-1 Envelope trimer by V1V2 loop-targeting antibodies

“…Quaternary interactions visualized thus far for V1V2 bNAbs involve the binding of a single Fab to the apex of Env trimer (Julien et al, 2013b; Liu et al, 2017), but here we demonstrate that the stoichiometry of binding for the new V1V2 bNAb BG1 (Freund et al, 2017) is two Fabs per Env trimer, with a minor population of 3:1 BG1-Env complexes (Figures 2 and 3; Figure 3—figure supplement 1). …”

T-bet-expressing B cells during HIV and HCV infections

“…By directly tying the presence of B cells and neutralizing antibodies to maintenance of steady-state plasma viremia, these studies suggest that the humoral immune response helps to establish and preserve a balance between host and HIV/SIV. Lastly, while natural control of viremia is considered to be mediated mostly by CD8 T cells, humoral immunity may contribute in certain cases [115,116]. In summary, antibodies put significant pressure on the virus and appear to play a role in maintaining at least partial control of HIV viremia.…”

Association of HIV-1 Gag-Specific IgG Antibodies With Natural Control of HIV-1 Infection in Individuals Not Carrying HLA-B*57:01 Is Only Observed in Viremic Controllers

“…Recently, Koofhethile et al [5] demonstrated that viremic controllers (VCs) not carrying ‘protective’ alleles of HLA-B genes control HIV-1 infection more robustly than carriers, and that CD8 + T cells do not mediate this effect. In addition, Freund et al [6] demonstrated that HIV-1 Env-specific antibodies with broad neutralising activity might have contributed to long-term control of HIV-1 infection in an elite controller (EC) who carried the ‘protective’ HLA-B alleles HLA-B*57:01 and HLA-B*27:05. However, the findings of previous studies on the role of antibodies in the natural control of HIV-1 infection have been inconclusive [2, 7–11].…”