Broadly Cross-Neutralizing Antibodies in HIV-1 Patients with Undetectable Viremia

Abstract

Several recent studies have identified HIV-infected patients able to produce a broad neutralizing response, and the detailed analyses of their sera have provided valuable information to improve future vaccine design. All these studies have excluded patients on antiretroviral treatment and with undetectable viral loads, who have an improved B cell profile compared to untreated patients. To better understand the induction of neutralizing antibodies in patients on antiretroviral treatment with undetectable viremia, we have screened 508 serum samples from 364 patients (173 treated and 191 untreated) for a broadly neutralizing antibody (bNAb) response using a new strategy based on the use of recombinant viruses. Sera able to neutralize a minipanel of 6 recombinant viruses, including envelopes from 5 different subtypes, were found in both groups. After IgG purification, we were able to confirm the presence of IgG-associated broadly neutralizing activity in 3.7% (7 of 191) of untreated patients with detectable viremia and 1.7% (3 of 174) of aviremic patients receiving antiretroviral treatment. We thus confirm the possibility of induction of a broad IgG-associated neutralizing response in patients on antiretroviral treatment, despite having undetectable viremia. This observation is in stark contrast to the data obtained from long-term nonprogressors, whose little neutralizing activity has been attributed to the low levels of viral replication.

Evolution of Broadly Cross-Reactive HIV-1-Neutralizing Activity: Therapy-Associated Decline, Positive Association with Detectable Viremia, and Partial Restoration of B-Cell Subpopulations

“…Neutralization breadth has been positively correlated with plasma viral load (5,9,13,14). However, this correlation contrasts with our report in which broad neutralizing responses were detected in patients on combination antiretroviral therapy (cART), despite having undetectable viremia (15). A better understanding of how broadly cross-reactive neutralizing activity (bCrNA) develops and evolves in infected patients may provide important clues for vaccine design.…”

“…Medical visits were scheduled at approximately 6-month intervals or more often as necessary for appropriate clinical care. bCrN individuals were identified previously (15), and control patients were selected on the basis of having shown no significant neutralization breadth in the previous cross-sectional study. Control patients were also matched for age (25 to 57 years old), CD4 ϩ counts (291 to 759 cells/l), CD8…”

“…Purified IgGs were tested at a 0.2-mg/ml concentration (corresponding to a dilution range of 1/40 to 1/80) against a minipanel of 6 recombinant viruses from different tropisms and 5 different subtypes using TZM-bl cells, as previously described (15). Serial IgG concentrations (0.3 to 0.001 mg/ml) from patients 181, 308, and 528 were also tested against the same recombinant virus panel.…”

“…In that study (15), we identified 12 patients that were capable of neutralizing viruses across 5 subtypes (here termed broadly cross-neutralizing [bCrN] patients). We were also able to confirm the presence of broadly IgG-associated cross-reactive neutralizing responses in a group of patients on antiretroviral treatment, despite their having undetectable viremia (15). In the present study, we evaluated the evolution of neutralization breadth in a group of 6 previously identified bCrN and 6 control patients for a 6-year period.…”

“…In a previous cross-sectional study (15), we screened 508 serum samples from 364 patients (173 treated and 191 untreated) for broadly cross-reactive neutralizing activity using a strategy based on the use of recombinant viruses. In that study (15), we identified 12 patients that were capable of neutralizing viruses across 5 subtypes (here termed broadly cross-neutralizing [bCrN] patients).…”