Exposure to common infections may shape basal immunity and potentially HIV-1 acquisition amongst a high-risk population in Coastal Kenya
Lynn Fwambah 1,2 Cheryl Andisi 2, Claire Streatfield 3, Rachel Bromell3, Jonathan Hare3,4, Joakim Esbjörnsson5 ,6, Thumbi Ndung’u 7,8,9,10, Eduard J. Sanders1,6,11, Amin S. Hassan1,5 and Eunice Nduati1,2*† 1. Kenya Medical Research Institute (KEMRI)/Wellcome Trust Research Programme, Kilifi, Kenya 2. Department of Biological Sciences, Pwani University, Kilifi, Kenya 3. International AIDS Vaccine Initiative (IAVI) Human Immunology Laboratory, Imperial College, London, United Kingdom 4. International AIDS Vaccine Initiative (IAVI), New York, NY, United States 5. Department of Translational Medicine, Lund University, Lund, Sweden 6. Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom 7. Africa Health Research Institute (AHRI), Durban, KwaZulu-Natal, South Africa 8. Human Immunodeficiency Virus (HIV) Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa 9. Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA, United States 10. Division of Infection and Immunity, University College London, London, United Kingdom 11. The Aurum Institute, HIV Division, Johannesburg, South Africa
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Introduction: The impact of exposure to endemic infections on basal immunity and susceptibility to HIV-1 acquisition remains uncertain. We hypothesized that exposure to infections such as cytomegalovirus (CMV), malaria and sexually transmitted infections (STIs) in high-risk individuals may modulate immunity and subsequently increase susceptibility to HIV-1 acquisition.
Methods: A case-control study nested in an HIV-1 negative high-risk cohort from Coastal Kenya was used. Cases were defined as volunteers who tested HIV-1 positive during follow-up and had a plasma sample collected 3 ± 2 months prior to the estimated date of HIV-1 infection. Controls were individuals who remained HIV-1 negative during the follow-up and were matched 2:1 to cases by sex, age, risk group and follow-up time. STI screening was performed using microscopic and serologic tests. HIV-1 pre-infection plasma samples were used to determined exposure to CMV and malaria using enzyme-linked immunosorbent assays and to quantify forty-one cytokines and soluble factors using multiplexing assays. Multiplexing data were analyzed using principal component analysis. Associations between cytokines and soluble factors with subsequent HIV-1 acquisition were determined using conditional logistic regression models.
Results and discussion: Overall, samples from 47 cases and 94 controls were analyzed. While exposure to malaria (p=0.675) and CMV (p=0.470) were not associated with HIV-1 acquisition, exposure to STIs was (48% [95% CI, 33.3 – 63] vs. 26% [95% CI, 17.3 – 35.9]. Ten analytes were significantly altered in cases compared to controls and were clustered into four principal components: PC1 (VEGF, MIP-1β, VEGF-C and IL-4), PC2 (MCP-1, IL-2 and IL-12p70), PC3 (VEGF-D) and PC4 (Eotaxin-3). PC1, which is suggestive of a Th2-modulatory pathway, was significantly associated with HIV-1 acquisition after controlling for STIs (adjusted odds ratio, (95% CI), p-value: 1.51 [1.14 – 2.00], p=0.004). Elevation of Th2-associated pathways may dampen responses involved in viral immunity, leading to enhanced susceptibility to HIV-1 acquisition. Immunomodulatory interventions aimed at inhibiting activation of Th2-associated pathways may be an additional strategy to STI control for HIV-1 prevention and may reduce dampening of immune responses to vaccination.
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