# Telomere attrition and T cell aging in vaccine failure during HIV infection

> **NIH VA I01** · JAMES H QUILLEN VA MEDICAL CENTER · 2024 · —

## Abstract

SUMMARY
The overall goal of this proposal is to elucidate the mechanisms by which chronic HIV infection promotes telomere
attrition and T cell aging, leading to hepatitis B virus (HBV) vaccine hypo-responsiveness. To this end, we will use a
model that emulates HBV vaccine response in the setting of HIV infection. Since co-infection of HBV with HIV is
common and associated with an increased morbidity and mortality, HBV vaccine is required to prevent HBV co-
infection in HIV patients. However, HBV vaccine response in HIV-infected patients is often blunted with only 30-60%
seroconversion (HBsAb > 10 IU/ml) compared to 90-95% success rate in age-matched healthy subjects (HS). This
poor vaccine response is also observed with influenza and pneumococcal vaccinations in HIV patients and other
immunocompromised hosts, including the elderly. Recently, we have found that chronic HIV or HCV infection can
cause premature T cell aging, as evidenced by overexpression of the aging markers KLRG1, DUSP6, CD57, and
p16ink4a, dysregulation of age-associated noncoding RNAs GAS5/miR21 and, in particular, accelerated telomere
attrition - suggesting excessive proliferative turnover or inadequate telomere maintenance. Telomere integrity is a
key feature of linear chromosomes that preserves genomic stability and function, whereas telomere attrition is a
hallmark of cell aging or senescence that drives cell dysfunctions and apoptosis. While telomere length is maintained
in most cases by a telomerase that prolongs telomeric DNA, telomere-associated proteins (shelterins) protect
telomeres from unwanted DNA damage response (DDR). We investigated the mechanisms of telomere attrition in
the setting of HCV and HIV infections and discovered that the cellular expression and activity of telomerase are
intact, whereas the telomeric repeat binding factor 2 (TRF2) is significantly inhibited in CD4 T cells derived from
HCV- or HIV-infected patients. Since the role of TRF2 is to protect telomeres from unwanted DNA damage and
recruit DNA repair enzymes (e.g., telomerase) access/function at telomeres, we hypothesize that: i) the mechanisms
involved in TRF2 inhibition may accelerate telomere attrition and CD4 T cell aging during HIV infection; ii) TRF2
inhibition may result in poor access/function of telomerase at telomeres during HIV infection; and iii) TRF2-mediated
telomere attrition and CD4 T cell aging may play a pivotal role in the failure of HBV vaccine in HIV-infected patients.
To test this hypothesis, we will 1) define the mechanisms involved in TRF2 inhibition and telomere attrition in T cell
aging during HIV infection; 2) determine how TRF2-mediated telomerase transport to telomeres affects T cell aging
during HIV infection; and 3) determine the impact of telomere attrition and T cell aging on HBV vaccine failure during
HIV infection and whether restoring TRF2-mediated telomere sheltering and telomerase homing machinery can
rescue CD4 T cells from telomere attrition and restore ...

## Key facts

- **NIH application ID:** 10816442
- **Project number:** 5I01BX002670-07
- **Recipient organization:** JAMES H QUILLEN VA MEDICAL CENTER
- **Principal Investigator:** Zhi Q. Yao
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816442

## Citation

> US National Institutes of Health, RePORTER application 10816442, Telomere attrition and T cell aging in vaccine failure during HIV infection (5I01BX002670-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10816442. Licensed CC0.

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