# The push and pull of inflammation on HIV susceptibility: impact of host variation in CD101 and AXL > **NIH NIH R01** · UNIVERSITY OF WASHINGTON · 2024 · $814,933 ## Abstract ABSTRACT Despite the significant public health impact of highly active antiretroviral therapy and pre-exposure prophylaxis on the HIV-1 pandemic, fundamental questions remain about the biological mechanisms that define the risk of sexually acquiring HIV-1. Notably, there is no explanation why, after accounting for genetic variants that directly modify HIV-1 entry and replication (foremost CCR5Δ-32), individuals with documented high exposure to HIV- 1 exhibit diverse outcomes ranging from rapid infection to prolonged natural resistance to HIV-1 infection. A better understanding of these phenotypes could lead to novel interventions to reduce HIV-1 acquisition. We previously identified functional variants (missense/nonsense, untranslated region, or splice site) in host genes that are strongly associated with altered risk of heterosexually acquired HIV-1 infection. Notably, genetic variants in CD101 had the strongest association with increased HIV-1 risk, while variants in AXL had substantially reduced risk. Both genes are thought to regulate host inflammatory responses. CD101 regulates T cell activation and is expressed on many immune cell types. We recently reported that circulating T cells and monocytes from donors with these CD101 variants, compared to donors without functional CD101 variants, show higher overall cellular activation, but with reduced expression of certain HIV-protective interferon stimulated genes. In contrast, AXL is a receptor tyrosine kinase thought to act through myeloid cells to inhibit cellular immune activation, possibly through inhibition of toll-like receptor-mediated innate immune responses. Our overarching hypothesis is that host variation in CD101 and AXL genotypes contributes to altered inflammatory homeostasis, thereby influencing the risk of HIV-1 infection. Specifically, we hypothesize that CD101 variants confer a higher risk of HIV-1 infection by increasing the abundance and activation of HIV-1 susceptible T cells, while also compromising their innate antiviral defenses. Conversely, the absence of these variants, possibly augmented by reduced inflammation conferred by AXL variants, lowers HIV-1 infection risk. We propose to evaluate our hypothesis in three aims: in Aim 1, we use genomic data from a cohort with well- characterized HIV-1 acquisition phenotypes to replicate in a second high HIV-risk African cohort that AXL variants balance the impact of CD101 variants on HIV-1 susceptibility. In Aim 2, we test the epidemiological and population generalizability of our hypothesis by quantifying the association of CD101 and AXL variation with susceptibility to HIV-1 infection in two US populations for which genomic data already exist: one that includes predominantly white men who have sex with men; and a second, ethnically diverse cohort recruited across the entire US. In Aim 3, we apply molecular techniques to blood and genital mucosal samples archived in a unique biospecimen repository to directly link the presence ... ## Key facts - **NIH application ID:** 10911799 - **Project number:** 5R01AI172479-03 - **Recipient organization:** UNIVERSITY OF WASHINGTON - **Principal Investigator:** Florian Hladik - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $814,933 - **Award type:** 5 - **Project period:** 2022-07-12 → 2027-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10911799 ## Citation > US National Institutes of Health, RePORTER application 10911799, The push and pull of inflammation on HIV susceptibility: impact of host variation in CD101 and AXL (5R01AI172479-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10911799. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*