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ABSTRACT & COMMENTARY

Inhibition of Telomerase Activity by NRTI’s may Contribute to Accelerated Aging in HIV Patients

June 1, 2013
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By Dean L. Winslow, MD, FACP, FIDSA, Chairman, Department of Medicine, Santa Clara Valley, Medical Center; Clinical Professor, Stanford University School of Medicine, Associate Editor of Infectious Disease Alert. Dr. Winslow is a consultant for Siemens Diagnostic. Abstract and commentary by Dean L. Winslow, MD, FACP, FIDSA

Synopsis: Nucleoside and nucleotide analogues inhibit telomerase activity and leads to shortening of telomere length (TL) in activated PBMC’s in culture.

Source: Leeansyah E, et al. Inhibition of telomerase activity by human immunodeficiency virus (HIV) nucleos(t)ide reverse transcriptase inhibitors: a potential factor contributing to HIV-associated accelerated aging. JID 2013;1157-65.

Telomerase activity and telomere length (TL) were measured by quantitative PCR in vitro in activated peripheral blood mononuclear cells (PBMC’s) cultured with NRTI’s and in PBMC’s from uninfected patients as well as PBMC’s from HIV-infected patients receiving NRTI-containing cART. Lamivudine, abacavir, emtricitabine, and tenofovir all significantly inhibited telomerase activity in activated PBMC’s in vitro. Tenofovir (TDF) was the most potent telomerase inhibitor and caused the greatest telomere shortening at clinically-achievable concentrations (0.3uM). PBMC’s from patients receiving NRTI’s had significantly lower telomerase activity than PBMC’s from HIV-uninfected patients. In HIV-infected patients receiving non-NRTI-containing cART, TL was inversely associated with age and total duration on any NRTI in the past. TL in PBMC’s from uninfected controls did not appear to be related to age.

Commentary

I always look forward to reading papers from the Australian group since they seem to consistently do such careful and interesting translational research in the field of HIV. This paper is no exception.

Over the last several years there has been increasing attention paid to non-AIDS-defining illnesses in HIV patients including malignancy, cardiovascular disease, and bone disease. A cellular correlate of human aging is progressive shortening of telomere length with cell division. Telomeres are located at the ends of chromosomes and consist of short, tandem, G-rich hexanucleotide repeats. During mitotic cell division, telomere DNA is not duplicated by DNA polymerase and undergoes progressive shortening until a critical length is reached and the cells enter replicative senescence. Several studies have shown a correlation between TL in PBMC’s and diseases of aging including cardiovascular disease and dementia. TL is maintained by telomerase (a ribonucleoprotein enzyme complex containing a telomerase RT subunit). AZT, ddI, and abacavir have previously been shown to inhibit telomerase activity in replicating cell lines in vitro and cause accelerated shortening of TL. This has been felt to be due to NRTI inhibition of telomerase RT activity (TERT) via chain termination, similar to their mechanism of action against retroviral RT. However, other mechanisms may play a role as well. This study demonstrates that the newer NRTI’s have similar effects on telomerase activity and TL in PHA-activated PBMC’s, which may be more relevant than effects observed in T-cell lines.

This study is thought-provoking for several reasons. Despite the wonderful impact of HAART on reversing immunosuppression, reducing the prevalence of classic AIDS-defining infections and malignancies and prolonging life in patients infected with HIV, it is clear that cART does not completely prevent all of the complications seen in HV-infected patients. Despite cART, patients with HIV still experience greater risk of cardiovascular disease than HIV-negative individuals, experience more rapid progression of HBV and HCV-related disease, and an increased prevalence of many cancers including Hodgkin lymphoma and HPV-related cancers. Many clinicians believe that some of these effects are related to “accelerated aging.” However the relative contributions of increased inflammatory cytokines (probably related to increased gut microbial translocation despite effective cART), HIV itself, and the effects of antiretroviral therapy are not clear. The demonstration that one of our preferred NRTI’s (tenofovir) may directly contribute to “accelerated aging” by its effect on inhibition of telomerase bears further study.