A Cytokine Pattern That Differentiates Preseroconversion From Postseroconversion Phases of Primary HIV Infection

Abstract

Background: During acute HIV infection, HIV actively replicates but seroconversion has not yet occurred. Primary HIV infection (PHI) is characterized by a transient nonspecific febrile illness, a massive inflammatory response, and the progressive appearance of anti-HIV-specific antibodies. In this study, we have identified patterns of inflammatory biomarkers associated with the innate immunological reaction before completion of a full humoral response.Methods: A symptom-based screening was used to identify acute HIV infection in the Manhiça District Hospital in Mozambique. Plasma levels of biomarkers were determined by Luminex and enzyme-linked immunosorbent assay. Anti-HIV antibodies were analyzed by flow cytometry and Western blot. Statistical analyses used random forest and logistic regression models.Results: Of 3116 rapid test seronegative or indeterminate individuals, 85 (2.7%) had positive plasma HIV viral load and were enrolled as PHI, of which n = 45 (52.9%), n = 8 (9.4%), n = 12 (14.1%), and n = 20 (23.5%) were classified as Fiebig I-III, IV, V, and VI stages, respectively, by Western blot. Comparison of individuals at early (Fiebig I-IV) and late (Fiebig V-VI) immune stages identified significant differences in the expression level of plasma B-cell activating factor , monocyte chemotactic protein-1, sCD163, and monokine induced by interferon (IFN-g). This cytokine signature classified patients in the preseroconversion phase with a sensitivity of 92.5% and a specificity of 81.2%Conclusions: Identification of a cytokine signature specific for the preseroconversion stage of PHI may help to understand the earliest HIV pathogenic events and identify new potential targets for immunotherapy aimed at modulating the cytokine response to HIV infection.

IP-10 Levels as an Accurate Screening Tool to Detect Acute HIV Infection in Resource-Limited Settings

“…The study population was enrolled between 2013 and 2014 at the MDH in Mozambique. The present analysis is a sub-study of a prospective cohort of primary HIV-infected adults enrolled 15 and followed up for 12 months in the Gastro-intestinal biomarkers in AHI Mozambican Adults study (GAMA). This study was approved by local institutional review boards at Barcelona Clinic Hospital (2011/6264) and by the Ministry of Health of Mozambique (461/CNBS/12).…”

“…Technical information and procedures regarding HIV diagnosis, clinical follow up, HIV-specific antibody determination and biomarker quantification have been previously described 15 . Individuals presenting to the outpatient clinic of MDH with reported fever, flu-like symptoms or malaria suspicion were included in the AHI group of this sub-study if they were HIV-rapid test seronegative and HIV-RNA positive.…”

“…A control population was established by random selection among NIF and their screening samples were employed to compare cytokine expression levels with the AHI group. At an additional visit, non-febrile HIV-uninfected controls (n = 58) provided samples that were used to establish biomarker reference levels in the absence of fever illness 15 . HIV-specific serology was performed by Western Blot.…”

“…The current gold-standard test for confirming viraemia is RT-PCR for plasma HIV-RNA 11 . However, technical and financial constraints make this technique very limited in low-income areas 1 such as Sub-Saharan Africa (SSA), where the prevalence of AHI among febrile patients may reach 3% 13 – 15 .…”

Association between the cytokine storm, immune cell dynamics, and viral replicative capacity in hyperacute HIV infection

“…HIV infection is associated with immune activation which manifests in the elevation of numerous plasma cytokines and chemokines [1][2][3][4][5][6][7]. Notably, the elevation of some plasma cytokines occurs very early after infection, with acute HIV infection (AHI) being characterized by the onset of a cytokine storm in the period leading up to peak viremia [1,2,4,6]. The resolution of the cytokine storm following peak viremia is partial, with some cytokines remaining elevated above pre-infection physiologic levels which persist into the chronic phase in untreated infection.…”