# Loss of Y-chromosome as a driver of HIV-1 latency

> **NIH NIH R56** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2023 · $424,254

## Abstract

ABSTRACT
 The presence of extensive heterogeneity between individual latently HIV-1 infected T cells suggests that
latent HIV-1 infection can persist under greatly differing host cell conditions. While we and others have described
the biomolecular phenotype of latently infected T cells, the biomolecular driver(s) of these stable phenotypic
changes remain unknown. For primary T cells, the transition to a resting memory state or T cell exhaustion
effects may play a role, but latent infection is also found in naïve T cells or TfH cells suggesting additional
contributing mechanisms. Leading to this application, we addressed the question whether HIV infection can
trigger an irreversible modification of host cells that can explain the stability of latent infection events, and could
occur independent of memory status or CD4+ T cell subtype. We show that latently infected T cell lines and a
large percentage of in vitro generated latently infected primary T cells, when derived from male donors, exhibited
a Loss of Y-chromosome (LOY) phenotype. Numerical chromosomal aberrations, including the loss of sex
chromosomes, cause nonlinear transcriptomic changes, which would explain the observed extensive
transcriptomic heterogeneity between individual latently HIV-1 infected T cells. Extensive transcriptomic changes
can also result in impaired cellular signaling, and explain the widely differing reactivation response spectrum
between individual cells. For primary T cells, we demonstrate that latent HIV-1 infection events in LOY cells are
largely resistant to TCR/CD3-complex activation mediated reactivation, while latently infected T cells in
possession of their Y-chromosome promoted HIV-1 reactivation following TCR/CD3 activation. Loss of Y-
chromosome phenomena could thus explain the presence of a reactivation-resistant reservoir that has been first
described by the Siliciano group. As LOY is irreversible, this is the first report of a biomolecular alteration that
can mechanistically explain HIV-1 latency stability and reactivation inertness, which we consider the major hurdle
to viral eradication. In this application we will extend our studies on the correlation of LOY and reactivation
resistant HIV-1 latency. Our discovery provides us with the unique opportunity to separate the two phenotypic
parts of the latent reservoir based on a causative mechanism (LOY) that has functional consequences
(reactivation resistance), which will allow for the exploration and development of therapeutic strategies to
individually target these reservoir components using single cell analysis approaches (Aim 1). In parallel we will
investigate whether similar latency phenotypes can be found in T cells from female donors and whether loss of
X-chromosome (LOX), the most frequent numerical chromosomal aberration in females, plays a similar role for
HIV-1 latency control than LOY (Aim 2). The insights generated from this proposal should provide fundamental
new insights into HIV-1 laten...

## Key facts

- **NIH application ID:** 10882257
- **Project number:** 1R56AI179301-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** OLAF KUTSCH
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $424,254
- **Award type:** 1
- **Project period:** 2023-08-16 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882257

## Citation

> US National Institutes of Health, RePORTER application 10882257, Loss of Y-chromosome as a driver of HIV-1 latency (1R56AI179301-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882257. Licensed CC0.

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