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  • Despite all efforts for development

    2022-07-02

    Despite all efforts for development of reliable laboratory methods, according to WHO/UNAIDS technical update on HIV incidence assays, none of the assays evaluated by Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA) have completely met the criteria for an incidence assay (WHO/UNAIDS, 2013). The evaluated assays are based on maturation of immunologic response; the main factors challenging them include: variability in immune response among individuals, false recent status in individuals with long term infection, and variability by HIV subtypes and by population (WHO/UNAIDS, 2013). Most of the developed assays are based on evolution of antibody responses against HIV-1 during seroconversion period. Fiebig et al. showed that there is a consistent pattern of biomarker emergence during the seroconversion phase and that this pattern can be used to classify primary HIV infection into 6 distinct stages. According to their study, the last laboratory stage of seroconversion is a full-reactive western blot pattern, including the appearance of the integrase (p31) band (Fiebig et al., 2003). Integrase is one of the preserved and immunogenic products of pol gene (Allan et al., 1987); and the delayed antibody response against this antigen may lead to more accurate discrimination of recent and non-recent HIV infected individuals. Furthermore, because the affinity and avidity of produced rad001 evolve during time, detection of high avidity anti-integrase antibodies could improve the accuracy of diagnosis. High avidity antibodies can be detected by using chaotropic agents for dissociation of low avidity antibodies, decreasing the concentration of coated antigen, or combination of these two strategies (Wei et al., 2010).
    Materials and methods
    Results
    Discussion The best way for measurement of HIV incidence is monitoring non-infected but susceptible individuals during a specific period of time. In addition to high cost, this approach is associated with the risk of bias and needs the long-term follow up of a very large population (UNAIDS/WHO Working Group on Global HIV/AIDS and STI Surveillance, 2011). Hence, estimation of HIV incidence by cohort studies takes a long time and leads to outdated data. High speed and low cost are two remarkable advantages of HIV incidence laboratory tests over cohort studies. The majority of HIV incidence laboratory tests are based on evolving antibody responses against HIV antigens during time. In these tests, mean duration of recent infection, MDRI, is defined as the mean time required for crossing the cut-off point optical density. Higher MDRI leads to the more accurate discrimination with less probability of errors (Parekh and McDougal, 2005). Some HIV infected individuals need longer time to pass the cut-off point and some others always stay below this point, resulting in false recent classification. Variable immune responses between different subtypes and/or populations, suppression of the viral replication by ART or by immune system in elite controllers, decreased CD4+ T-cell count and, consequently, reduction of antibody titer during HIV progression, are the main factors associated with the false recent diagnosis in the laboratory incidence assays (Novitsky et al., 2009; Laeyendecker et al., 2012; Parekh et al., 2011). The selection of an appropriate antigen to study antibody responses for the classification of the infection period is very critical. In addition to immune-reactivity, this antigen should have a conserved sequence to cover different genotypes of HIV-1. The conservation is difficult to achieve because of the high inherent mutation rate of HIV. This problem can be resolved by using antigens covering multiple subtypes (Wei et al., 2010) or using conserved genes. In this study, we took the advantage of the conservation in integrase gene (Ceccherini-Silberstein et al., 2009). As our target population was Iranian patients, the integrase sequence of dominant subtype in Iran, CRF35_AD, was used. As it has been shown previously (Rikhtegaran Tehrani et al., 2015), there are only 5.9% differences between the sequence of CRF35_AD and that of HXB2 [GenBank accession number K03455] which is the most widely used reference strain of HIV. Most of the different residues are amino acids with similar physicochemical properties and hence percent similarity between these two sequences is 96.5%. Because of the high conservation of integrase gene, the assays were optimized based on specimens from non-CRF35_AD (PRB 601) and subsequently evaluated with sera from Iranian patients. The possible advantage of this conserved antigen is that it may provide the opportunity to use the developed assay for other population infected by different HIV-1 subtypes.