Jairam Lingappa

University of Washington

1 active project

HIV immunogenetic study

Despite the public health impact on the HIV-1 pandemic from highly active antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP), questions remain about the mechanisms that define risk of sexually acquired HIV. There is no explanation why after accounting for virus…

Scientific Questions Being Studied

Despite the public health impact on the HIV-1 pandemic from highly active antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP), questions remain about the mechanisms that define risk of sexually acquired HIV. There is no explanation why after accounting for virus exposure and presence of host variants modifying HIV-1 replication pathways, some highly exposed people exhibit resistance to HIV-1, while others are susceptible. Our studies suggest that a subset of immune response genes alters a person’s pro-inflammatory environment. We hypothesize that variants in these genes contribute to defining a homeostatic inflammation setpoint that impacts the risk of HIV-1 infection and other inflammatory disorders. Understanding these mechanisms could lead to novel interventions to reduce HIV-1 acquisition, along with other inflammatory conditions. We will evaluate the concept that aggregate host variation in two candidate genes modify risk of HIV-1 and other inflammatory disorders.

Project Purpose(s)

  • Disease Focused Research (HIV and other inflammatory conditions such as Type 1 and Type 2 diabetes)
  • Ancestry

Scientific Approaches

We will build three datasets. One includes HIV-infected cases (~5000 people) and HIV-uninfected controls. Many participants identified as HIV-uninfected are not highly HIV-exposed. Therefore, we will use Cox proportional hazards modeling to generate an HIV-risk score and use this to identify the HIV-uninfected in the highest 2% of HIV-exposure to include as controls. We will develop a dataset of Type 1 diabetes mellitus (T1D) cases with controls at high risk of T1D but who don’t have T1D, and a dataset of Type 2 diabetes mellitus (T2D) cases with controls at high risk of T2D but do not have s diagnosis. Whole genome sequence data will be used to test the association of aggregate functional genomic variants in our candidate genes with prevalence of HIV-1, T1D and T2D accounting for population structure. We will use the All of Us platform to access de-identified EHR, physical exam, and genomic data in a context that will protect the privacy of participants.

Anticipated Findings

To date no reproducible, underlying genetic mechanism has been identified that connects innate inflammation to HIV-risk. We hope to demonstrate that evaluation of aggregate variation in our two candidate genes can be used to define a homeostatic inflammation setpoint that impacts risk of HIV-1 infection and other inflammatory disorders. Our study will aid in understanding the pathways and mechanisms associated with susceptibility and natural resistance to HIV-1 infection, providing a framework for future host-targeted prevention measures and anti-inflammatory treatments based on a person’s constellation of homeostatic inflammation characteristics. Our research will also shed light on the burden of different rare variants contributing to HIV-susceptibility across various ethnicities and ancestries.

Demographic Categories of Interest

  • Race / Ethnicity
  • Gender Identity
  • Sexual Orientation

Research Team

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