Targeting the transcriptionally-active reservoir to reduce chronic inflammation in aged people with HIV

PROJECT SUMMARY Recent data suggest that a substantial fraction of the HIV reservoir persisting in the face of antiretroviral therapy (ART) is transcriptionally active and may contribute to the chronic inflammation observed in people with HIV (PWH). This is particularly pertinent in elderly PWH, who exhibit additional elevated inflammation and co-

morbidities due to the aging process itself. Surprisingly, immune differences between the sexes prove largest after the age of 65, an unexpected observation given that the menopausal transition in women (typically occurring between the ages of 45-55) decreases estradiol to levels similar to those of men. The extent to which biological

sex and sex steroids impact the HIV reservoir and chronic inflammation in elderly PWH has not been sufficiently studied. In this proposal, we will deeply characterize the transcriptionally-active HIV reservoir in aged ART- suppressed men and women with HIV, determine how these cells contribute to chronic inflammation, and identify

novel ways to block their ongoing viral gene expression. We will leverage the infrastructure of the MACS/WIHS Combined Cohort Study (MWCCS), and include not only virally suppressed men and women with HIV, but also those with non-suppressible viremia (NSV) as extreme cases of HIV transcriptional activity in the face of ART.

In Aim 1, we will use our newly developed single-cell sequencing-based technology, HIV-Seq, to compare the phenotypes, transcriptomes, and clonal expansion history of transcriptionally-active reservoir cells between elderly male and female participants, and between different tissue sites from aging women with HIV. In Aim 2,

we will use multiple “omics” technologies (CyTOF, Olink) to test the hypothesis that ongoing HIV gene expression drives chronic inflammation by fueling expansion of HIV- and CMV-specific CD4+ T cells harboring transcriptionally-active HIV. In Aim 3, we will identify novel ways to block ongoing HIV gene expression by

targeting the accessory protein Tat, and test the consequences of this blockade in primary cell models and using patient specimens. Collectively, our aims will help develop strategies to prevent the expansion of the transcriptionally-active reservoir in aging male and female individuals living with HIV and identify drugs that

durably silence HIV expression in reservoir cells. Our inclusion of post-menopausal women is a notable innovation, as women have been historically understudied even though they shoulder a large burden of the HIV epidemic.