Abstract
Accurate HIV-1 incidence estimation is critical to the success of HIV-1 prevention strategies. Current assays are limited by high false recent rates (FRRs) in certain populations and a short mean duration of recent infection (MDRI). Dynamic early HIV-1 antibody response kinetics were harnessed to identify biomarkers for improved incidence assays. We conducted retrospective analyses on circulating antibodies from known recent and longstanding infections and evaluated binding and avidity measurements of Env and non-Env antigens and multiple antibody forms (i.e., IgG, IgA, IgG3, IgG4, dIgA, and IgM) in a diverse panel of 164 HIV-1-infected participants (clades A, B, C). Discriminant function analysis identified an optimal set of measurements that were subsequently evaluated in a 324-specimen blinded biomarker validation panel. These biomarkers included clade C gp140 IgG3, transmitted/founder clade C gp140 IgG4 avidity, clade B gp140 IgG4 avidity, and gp41 immunodominant region IgG avidity. MDRI was estimated at 215 day or alternatively, 267 days. FRRs in untreated and treated subjects were 5.0% and 3.6%, respectively. Thus, computational analysis of dynamic HIV-1 antibody isotype and antigen interactions during infection enabled design of a promising HIV-1 recency assay for improved cross-sectional incidence estimation.
Highlights
Accurate estimates of HIV-1 incidence are critical for planning and evaluating the success of HIV-1 prevention strategies [1, 2]
To harness this information for an HIV-1 incidence assay, we tested different antibody forms (i.e., IgM, IgG, IgG3, IgG4, IgA) in concert with a wide variety of HIV-1 antigens to comprehensively cover the epitopes and antigen structures most likely to be reactive with immune sera from recent to chronic infection, including transmitted/ founder envelope (T/F) proteins [22,23,24,25,26]
We evaluated a diverse set of antibody-antigen combinations to develop a combination of biomarkers for improved HIV-1 incidence estimation
Summary
Accurate estimates of HIV-1 incidence (i.e., the number of new HIV infections in a population in a defined period of time) are critical for planning and evaluating the success of HIV-1 prevention strategies [1, 2]. The WHO/UNAIDS Incidence Assay Critical Path Working Group [2, 14] recommends an ideal MDRI of between 6 and 12 months after infection with a FRR < 2%. Achievement of these goals is critical to the accurate assessment of HIV-1 treatment and prevention efforts, the design of HIV-1 vaccine trials, and monitoring the epidemic in pursuit of an AIDS-free generation
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