Abstract
BackgroundA blood-based assay that could quantify HIV susceptibility would be very valuable for HIV prevention research. Previously, we developed and validated an ex vivo, flow-based, HIV entry assay to assess genital HIV susceptibility in endocervical CD4+ T cells.MethodsHere we assessed whether this tool could be used to predict HIV risk using blood-derived CD4+ T cells in a rigorously-blinded, nested case-control study using blood samples collected from high-risk, HIV-uninfected South African women enrolled in the CAPRISA 004 clinical trial. Cases, subsequently acquiring HIV were sampled prior to HIV infection and compared with controls, who remained HIV-uninfected. The primary endpoint was ex vivo entry of a CCR5-tropic HIV founder virus into blood CD4+ T cells. Secondary endpoints included HIV entry into CD4+ central (TCM) and effector (TEM) memory T cells, and into CD4+ T cell subsets expressing CCR5, CD69, CCR6, α4β1 or α4β7.ResultsCompared to bulk CD4+ T cells (4.9% virus entry), CD4+ T cells expressing CCR5, CCR6 or α4β1 and TEM were highly susceptible (15.5%, 8.8%, 8.2% and 10.8% entry, respectively, all p<0.0001), while TCM, CD69+ or α4β7+ CD4+ cells were moderately susceptible (6.4%, 6.0% and 5.8% respectively, p ≤ 0.003). While the proportion of the aforementioned highly susceptible cells correlated with overall virus entry into CD4+ T cells within an individual (r = 0.68, 0.47, 0.67, and 0.60 respectively, p<0.0001), blood virus entry did not predict subsequent mucosal HIV acquisition after controlling for sexual behaviour and condom use (OR 0.92, 95% CI 0.77–1.11, p = 0.40).ConclusionsAlthough virus entry identified several previously known highly susceptible cellular HIV targets, blood HIV entry did not predict subsequent heterosexual HIV acquisition. Assessment of mucosal HIV susceptibility may require sampling at the site of HIV exposure.
Highlights
There were approximately 1.4 million new HIV infections in Sub-Saharan Africa (SSA) in 2015, most of which were acquired in women through receptive vaginal sex [1]
We developed and validated an ex vivo, flow-based, HIV entry assay to assess genital HIV susceptibility in endocervical CD4+ T cells. We assessed whether this tool could be used to predict HIV risk using blood-derived CD4+ T cells in a rigorously-blinded, nested case-control study using blood samples collected from high-risk, HIV-uninfected South African women enrolled in the CAPRISA 004 clinical trial
Assessment of mucosal HIV susceptibility may require sampling at the site of HIV exposure
Summary
There were approximately 1.4 million new HIV infections in Sub-Saharan Africa (SSA) in 2015, most of which were acquired in women through receptive vaginal sex [1]. Heterosexual vaginal HIV acquisition is generally regarded to be inefficient, with per-contact risk of HIV infection ranging from 1/200-1/2000 sex acts [2] This inefficiency likely reflects the effectiveness of the mucosal host defenses including an intact epithelium, cervical mucus, immune cells (neutrophils, macrophages, T cells, dendritic cells, and others), and innate antimicrobial peptides (AMPs) such as alpha defensins and LL-37 [3]. An ex vivo HIV entry assay that directly quantifies virus entry into unstimulated cervical CD4+ T cells recently characterized genital and blood HIV target cells [12]. These included CD4+ T cells expressing CCR5 (HIV co-receptor), CD69 (early immune activation), α4β7 or α4β1 integrins (T cell homing) [12]. We developed and validated an ex vivo, flow-based, HIV entry assay to assess genital HIV susceptibility in endocervical CD4+ T cells
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