IMPACT OF PRE-EXISTING HOST CYTOKINE PROFILE AND PATHOGEN EXPOSURE ON SUBSEQUENT HIV-1 ACQUISITION IN A HIV-1 HIGH RISK POPULATION IN COASTAL KENYA

Abstract

Background: Pathogenic bacterial, viral, parasitic and fungal infections comprise the biggest burden of disease in sub-Saharan Africa (sSA). Constant exposure to these infections has been reported to lead to an altered immune response, which has been associated with reduced vaccine responses and increased risk of acquisition of secondary infections. Whether altered immune responses increase susceptibility to HIV-1 acquisition in the sSA setting remains less well documented. This study hypothesized that exposure to common pathogens results in elevated immune activation, leading to an increased risk of HIV-1 acquisition. Methods: A case-cohort study design was used. High-risk HIV-1 negative volunteers were followed up longitudinally. Cases and controls were defined as volunteers who acquired and those who did not acquire HIV-1 infection during a 3-month follow up, respectively. For cases, plasma samples collected 3(+/-1) months before HIV-1 infection were identified. Controls were matched 2:1 to cases by gender, age, risk group and follow-up time from enrolment into the cohort. Immune activation was determined by measuring 37 analytes using the Meso-Scale Discovery platform. IgG antibody levels against two common pathogens in the region, malaria and cytomegalovirus (CMV) were also measured using enzyme-linked immunosorbent assay (ELISA). Immune activation markers and pathogen exposure levels were then compared between cases and controls. Analytes that were significantly different between cases and controls were carried forward to principal component analysis (PCA) to delineate clustering patterns to help explain underlying related biological pathways. Further, principal components were taken forward to linear regression models to determine their association with HIV-1 acquisition. Results: Overall, 141 samples from cases (n=47) and controls (n=94) were analyzed. Amongst the cytokines measured, MIP-1β (p=0.04), Eotaxin-3 (p=0.02), IL-12p70 vi (p=0.04), IL-2 (p=0.02), and IL-4 (p=0.008) were significantly elevated among cases compared to controls, while VEGF-D (p=0.049) was significantly lower in cases. Using PCA, analytes were disentangled into four clusters: PC1 (comprising VEGF, MIP-1β, VEGF-C and IL-4), PC2 (comprising MCP-1β, IL-2 and IL-12p70), PC3 (comprising VEGF-D) and PC4 (comprising Eotaxin-3). In regression analysis, PC1 (suggestive of a Th2 profile, p=0.004) and PC3 (suggestive of tissue repair function, p=0.04) were independently associated with HIV-1 acquisition. Further, there were no significant differences between cases and controls on IgG antibody titres against malaria (p=0.47) and CMV (p=0.68). Although IL-1α (p=0.03), IL-5 (p=0.02), and IL-10 (p=0.02) were significantly higher in malaria seropositive than malaria seronegative volunteers, exposure to malaria and CMV were not significantly associated with the observed immune activation. Conclusion: An altered cytokine profile was observed in cases compared to controls, over similar follow-up duration. Th2 and tissue repair pathways may play a role in increasing and decreasing susceptibility to HIV-1 acquisition, respectively. While malaria and CMV are common in this region, neither was associated with the observed cytokine profile implying that these two infections may not be the only drivers of the immune activation profile observed. The cytokine signal identified in this study warrants comprehensive systems analysis approaches to identify factors that may predispose one to HIV-1 acquisition, particularly in Africa where constant exposure to many infections results in immunomodulation.