Broadly neutralizing antibodies (bnAbs) against highly variable viral pathogens are much sought-after to treat or protect against global circulating viruses. We have probed the neutralizing antibody repertoires of four HIV-infected donors with remarkably broad and potent neutralizing responses and rescued 17 new monoclonal antibodies (MAbs) that neutralize broadly across clades. Many of the new MAbs are almost 10-fold more potent than the recently described PG9, PG16, and VRC01 bnMAbs and 100-fold more potent than the original prototype HIV bnMAbs1–3. The MAbs largely recapitulate the neutralization breadth found in the corresponding donor serum and many recognize novel epitopes on envelope (Env) glycoprotein gp120, illuminating new targets for vaccine design. Analysis of neutralization by the full complement of anti-HIV bnMAbs now available reveals that certain combinations of antibodies provide significantly more favorable coverage of the enormous diversity of global circulating viruses than others and these combinations might be sought in active or passive immunization regimes. Overall, the isolation of multiple HIV bnMAbs, from several donors, that, in aggregate, provide broad coverage at low concentrations is a highly positive indicator for the eventual design of an effective antibody-based HIV vaccine.

To determine the protective potential of the humoral immune response against HIV-1 in vivo we evaluated the potency of three neutralizing antibodies (2G12, 2F5 and 4E10) in suppressing viral rebound in six acutely and eight chronically HIV-1-infected individuals undergoing interruption of antiretroviral treatment (ART). Only two of eight chronically infected individuals showed evidence of a delay in viral rebound during the passive immunization. Rebound in antibody-treated acutely infected individuals upon cessation of ART was substantially later than in a control group of 12 individuals with acute infection. Escape mutant analysis showed that the activity of 2G12 was crucial for the in vivo effect of the neutralizing antibody cocktail. By providing further direct evidence of the potency, breadth and titers of neutralizing antibodies that are required for in vivo activity, these data underline both the potential and the limits of humoral immunity in controlling HIV-1 infection.

Abstract1 2 6 0 VOLUME 22 | NUMBER 11 | NOVEMBER 2016 nature medicine a r t i c l e s bnAbs have become blueprints for vaccine design owing to their unequalled activity against divergent HIV-1 strains and proven potency in preventing and suppressing HIV-1 infection after in vivo administration [1][2][3][4][5][6][7][8] . Elicitation of potent bnAb activity is relatively rare in natural HIV-1 infection: only 10-25% of infected individuals develop breadth, and an estimated 1% generate highly potent bnAb, or 'elite neutralization' , activity 9,10 . Although much is known about the functional properties of bnAbs, the parameters that govern their evolution in natural infection remain unknown, which is a critical limitation for vaccine development. To date, no vaccine approach has induced bnAb responses that match those elicited in natural infection 1,11 . Defining what restricts and promotes bnAb evolution in certain individuals will be crucial for devising successful vaccine regimens, as the same restrictions are likely to be encountered during immunization.Observations that bnAb activity arises predominantly in viremic individuals after several years of infection and is linked to lower CD4 + cell counts (referred to here as CD4 levels) 4,12-14 strongly suggest that prolonged exposure to viral antigen is needed for induction of bnAbs.Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10 −5 ). Thus, key host, disease and viral determinants, including subtypespecific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.This may be necessary in part to allow the extensive antibody-affinity maturation that is characteristic of many HIV-1-specific bnAbs 15,16 . Similarly, antigen levels may be relevant, as bnAbs have been found to evolve less frequently in individuals with lower viral loads 1,4,13,17 . Individual case studies delineating pathways of bnAb maturation have highlighted the tight interplay between virus escape and antibody adaptation that precedes the development of a broad neutralization response [18][19][20][21][22][23] . In line with this, the viral envelop...