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    • HIV incidence is often determined by following cohorts of HI

    2021-09-26

    HIV incidence is often determined by following cohorts of HIV-uninfected individuals and quantifying the rate of new HIV infections. HIV incidence can also be estimated using a cross-sectional study design, using laboratory assays to identify individuals who are likely to have recent HIV infection. Most serologic assays used for cross-sectional HIV incidence estimation measure general characteristics of the antibody response to HIV infection (e.g., antibody titer, antibody avidity) (Murphy and Parry, 2008, Guy et al., 2009, Busch et al., 2010), which may be impacted by viral suppression, loss of CD4 T cells, and other factors (Laeyendecker et al., 2012b, Laeyendecker et al., 2012a, Kassanjee et al., 2014, Brookmeyer et al., 2013). We used the VirScan assay to identify peptide biomarkers associated with the duration of HIV infection, and demonstrated that peptide engineering can be used to enhance the properties of peptides for discriminating between early- and late-stage infection. This information could be used to develop improved methods for estimating HIV incidence from cross-sectional surveys, for surveillance of the HIV/AIDS epidemic (Justman et al., 2018), and for evaluating the impact of interventions for HIV prevention in clinical trials (Coates et al., 2014).
    Results
    Discussion We used the measure, “antibody breadth,” to quantify HIV antibody AGI-5198 and found that this measure reaches a plateau (“antibody breadth set point”) early in infection in individuals who do not start ART. In the GS study cohort, a decline in antibody breadth between 9 months and 2 years after infection was associated with a shorter time to ART initiation, which was prompted in the GS study cohort by a decline in CD4 cell count to <250 cells/mm3. The decline in antibody breadth among those who subsequently started ART likely reflected declining B cell support due to loss of T helper cells. HIV antibody breadth appeared to stabilize at a low level after ART initiation. In contrast, the breadth of the EBV antibody response increased sharply after ART initiation, which may have reflected immune reconstitution (Sharma and Soneja, 2011). While these observations provide important insights into the immune response to HIV infection, antibody breadth measurements generated with the VirScan assay are unlikely to be useful for monitoring HIV infection in clinical settings. Use of CD4 cell counts to monitor HIV disease progression is well established, and CD4 cell count data were more strongly correlated with time to ART initiation than antibody breadth in this study. Previous studies have identified several factors associated with HIV disease progression, including virologic factors (e.g., HIV viral load [Touloumi et al., 2013], replication capacity [Ng et al., 2014], and subtype [Baeten et al., 2007]), immunologic factors (e.g., inversion of the CD4/CD8 ratio [Margolick et al., 2006], polyclonality of the anti-HIV T cell response [Pantaleo et al., 1997], and degree of early immune activation [Fahey et al., 1990]), and host factors (e.g., human leukocyte antigen [HLA] type B57 [Costello et al., 1999] and CCR5 delta 32 mutations [Huang et al., 1996]). It is not clear whether the decline in antibody breadth that we observed caused disease progression leading to ART initiation, or whether it was a surrogate for other changes, such as a decline in T cell number or function. If the decline in antibody breadth has a causative role in disease progression, then use of therapeutic vaccines to boost antibody diversity may in theory provide clinical benefit. Generalized antibody responses to HIV infection, such as antibody titer and avidity, tend to plateau approximately 1 year after HIV infection (Busch et al., 2010). These characteristics of the antibody response are impacted by a variety of factors, including natural and drug-induced viral suppression (Koenig et al., 2013, Wendel et al., 2017, Kassanjee et al., 2014), disease progression (Laeyendecker et al., 2012b), and HIV subtype (Longosz et al., 2014, Longosz et al., 2015). Previous studies evaluating the banding pattern in western blots demonstrate that HIV antibody specificity evolves early in infection (Fiebig et al., 2003). Recent studies have explored whether assays that include a small number of protein or peptide targets could be used to identify recent HIV infections (Dotsey et al., 2015, Curtis et al., 2012). Using the VirScan assay to analyze 403 plasma samples, we were able to quantify antibody binding to >3,300 HIV peptides from early- to late-stage HIV infection. These data were used to generate a simple, unweighted, four-peptide model that predicted duration of HIV infection. Data from the prototype four-peptide model were more strongly correlated with duration than data from the LAg-avidity assay that is in wide use for cross-sectional HIV incidence estimation (Figure S4) (Wei et al., 2010).