Polyfunctionality and breadth of HIV-1 antibodies are associated with delayed disease progression

HIV-1 infection leads to chronic disease requiring life-long treatment and therefore alternative therapeutics, a cure and/or a protective vaccine are needed. Antibody-mediated effector functions could have a role in the fight against HIV-1. However, the properties underlying the potential beneficial effects of antibodies during HIV-1 infection are poorly understood. To identify a specific profile of antibody features associated with delayed disease progression, we studied antibody polyfunctionality during untreated HIV-1 infection in the well-documented Amsterdam Cohort Studies. Serum samples were analyzed from untreated individuals with HIV-1 at approximately 6 months (n = 166) and 3 years (n = 382) post-seroconversion (post-SC). A Luminex antibody Fc array was used to profile 15 different Fc features for serum antibodies against 20 different HIV-1 envelope glycoprotein antigens and the resulting data was also compared with data on neutralization breadth. We found that high HIV-1 specific IgG1 levels and low IgG2 and IgG4 levels at 3 years post-SC were associated with delayed disease progression. Moreover, delayed disease progression was associated with a broad and polyfunctional antibody response. Specifically, the capacity to interact with all Fc γ receptors (FcγRs) and C1q, and in particular with FcγRIIa, correlated positively with delayed disease progression. There were strong correlations between antibody Fc features and neutralization breadth and several antibody features that were associated with delayed disease progression were also associated with the development of broad and potent antibody neutralization. In summary, we identified a strong association between broad, polyfunctional antibodies and delayed disease progression. These findings contribute new information for the fight against HIV-1, especially for new antibody-based therapy and cure strategies.Author summary: Despite the availability of effective treatment, HIV-1 still causes significant mortality and morbidity across the globe. Alternative ways for protection or treatment against HIV-1 are needed. Antibody-mediated effector functions could potentially contribute to the effectiveness of novel approaches. However, we need more information on which antibody properties are associated with these potential beneficial functions of antibodies. Studying antibody responses during natural HIV-1 infection can provide guidance on this topic. This study identified several antibody properties that were associated with reduced HIV-1 disease progression in a large cohort of individuals with untreated HIV-1. High levels of IgG1 and low levels of IgG2 and IgG4, broad and polyfunctional antibodies and interaction with immune proteins FcyRs and C1q, were all associated with delayed disease progression. Subsequently, effective strategies against HIV-1 will likely require multiple different components, and the antibody properties described in this study may contribute to a more detailed bio-molecular roadmap for antibody-based strategies for HIV-1 prevention, therapy and cure.