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Senescence, Telomerase, Aging HIV
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from Jules: Immuno-senescence appears to set in shortly after HIV infection & perhaps achieving undetectable viral load & good CD4 increase provides some benefit but it clearly does not reverse this affect. Starting ART early as is now recommended by Guidelines will not prevent the aging problem either. Even with early cART inflammation & immune activation persist because it is HIV itself which causes this, it is the affect of HIV on the immune system & the metabolic system of an infected person that causes the immune dysregulation that causes aging problems: comorbidities, disabilities, brain disorders, etc . Early cART might soften the blow a little but it will not prevent the aging problem from affecting new generations with HIV. As well, the ARTs themselves contribute to the problems of aging with metabolic and immune affects. Even if we could treat all infected in acute infection the aging problem would persist. But we cannot treat in acute infection & in fact despite recommendations now to treat HIV immediately many HIV-infected for various reasons are not treated immediately, very early or even early. Treating even at 500 or 700 CD4s however will not prevent the aging problem. Inflammation & immune activation will persist and so will these affects discussed below. Mitochonndrial damage by HIV and by NRTIs & other ARTs are a concern & a question as it regards to aging in HIV and the premature or accelerated onset of comorbidities: bone, CVD, brain, etc. Telomerase research reports HIV damages & shortens telomerase. In HIV-negatives research shows shortened telomerase is associated with aging. Association of telomerase shortening with ARTs appear to show mixed results. Although older & more recent studies found telomerase shortening with old & newer NRTIs, there was a question regarding that in some of these studies showing an affect the therapeutic dose was not reached. This study from CROI 2017 below found NRTIs were associated in univariate analysis but not in multivariate analysis. So does the affect of current NRTIs cause clinically meaningful telomerase shortening, I am uncertain. Does stopping the older NRTIs stop the affect they had on shortening telomerase, I do not think we know. Oxidative stress appears to be associated with HIV & perhaps some ARTs. Metabolic complications appear to be associated with all ARTs, with integrase a possible exception. It is not very clear what are affects on telomerase & mitochondria by PIs, NNRTIs and NRTIS, affects may occur. What about affects of integrase on the brain. Myopathy, with raltegravir we see low rates CK increases. With statins some patients see similar affects with muscle discomfort & pain. All the integrases appear to have low incidence rates of CNS affects, although we do not know yet if bictegravir will have that affect. At IAS smoking & detectable viral load was associated with telomerase shortening, which both have been seen in several studies, so it appears that HIV shortens telomerase & undetectable viral load appears to provide some protection. Do NRTIs, NNRTIs & PIs affect telomerase? What about the affect of NNRTIs on the brain & CNS, they have an affect, in aging HIV+ what is the affect? It has been suggested the new NRTI Doravirine may not be associated with the typical CNS affects of NNRTIs, studies suggest this but it must be proven & established by followup research. I think this question remains unresolved. What are the longer-term affects of integrase inhibitors? Telomerase shortening by certain ARTs may contribute to accelerated or accentuated aging in HIV-infected. All these factors that contribute to premature or accelerated aging in HIV+ may cause a steeper decline as patients reach over 60 years old when aging & immune decline in HIV-negatives appears to take a steeper decline....."An important future clinical question will be to determine whether any inhibition of telomerase by NRTIs in vivo is reversible following cessation of NRTI. The long-term effects in HIV-infected patients of NRTI exposure on telomerase activity, TL, and accelerated aging warrant further investigation.....we have shown that DRV did not affect telomerase activity,hTERTgene expression, or hTERT protein levels.......Saquinavir has been demonstrated to upregulate telomerase activity in vitro [44, 45]. However, despite the possibility of saquinavir and therefore other PIs antagonizing NRTI-mediated telomerase inhibition in vivo, we still observed significantly lower telomerase activity in patients receiving NRTI-containing cART, suggesting that any upregulation of telomerase activity by PIs was not sufficient to overcome the inhibitory effect of NRTIs on telomerase activity." Recent studies show fat accumulation in many places in the HIV infected person including around the heart & in muscles, a metabolic disturbance affect. This will affect HIV+ aging muscles, CVD and likely extend beyond to the brain & worsen frailty - more and better research is needed to understand the affects and how bad it could get, and to understand the science of aging in HIV, and potential ways to prevent this crisis. There are a lot of questions including what are the safest regimens for older aging HIV+, but at this point in time there does not appear to be resolve by government officials and researchers in the USA to adequately address these critical issues. Healthcare costs for older aging HIV+ will increase 3-5 times; self-stigma is worse for them; how will we house large numbers of disabled HIV+? – with worsening cognitive and neurologic impairment will adherence become a big concern, I think it will for many. These problems will affect Western Europe; and where healthcare infrastructure in global HIV communities is not as strong the affects of the aging with HIV problem will be worse, much worse.
2014 paper - Aging and HIV/AIDS: pathogenetic role of therapeutic side effects - "Three important theories that explain the aging process are oxidative stress, telomerase inhibition and telomere shortening, and lamin A mutations and accumulations. Each directly, indirectly, or in combination relates to HIV/AIDS and side effects of HAART. For the purpose of this review, aging is defined as 'progressive deterioration of virtually every bodily function over time,' ultimately resulting in death. Abundant evidence supports the notion that aging is associated with mitochondrial dysfunction, decreased OXPHOS, and oxidative stress. Oxidative injury is integral to HIV/AIDS as a potent inducer of viral activation, viral replication, and DNA damage in infected cells.29, 30, 31, 32, 33 Clinically, HIV-1 infection is associated with a decrease in both intracellular and systemic glutathione (GSH).34, 35 This primary decrease in antioxidant defenses is the converse of increased oxidant production, but yields the same functional result"
ABSTRACT: The intersection of aging and HIV/AIDS is a looming 'epidemic within an epidemic.' This paper reviews how HIV/AIDS and its therapy cause premature aging or contribute mechanistically to HIV-associated non-AIDS illnesses (HANA). Survival with HIV/AIDS has markedly improved by therapy combinations containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors, and protease inhibitors (PIs) called HAART (highly active antiretroviral therapy). Because NRTIs and PIs together prevent or attenuate HIV-1 replication, and prolong life, the population of aging patients with HIV/AIDS increases accordingly. However, illnesses frequently associated with aging in the absence of HIV/AIDS appear to occur prematurely in HIV/AIDS patients. Theories that help to explain biological aging include oxidative stress (where mitochondrial oxidative injury exceeds antioxidant defense), chromosome telomere shortening with associated cellular senescence, and accumulation of lamin A precursors (a nuclear envelop protein). Each of these has the potential to be enhanced or caused by HIV/AIDS, antiretroviral therapy, or both. Antiretroviral therapy has been shown to enhance events seen in biological aging. Specifically, antiretroviral NRTIs cause mitochondrial dysfunction, oxidative stress, and mitochondrial DNA defects that resemble features of both HANA and aging. More recent clinical evidence points to telomere shortening caused by NRTI triphosphate-induced inhibition of telomerase, suggesting telomerase reverse transcriptase (TERT) inhibition as being a pathogenetic contributor to premature aging in HIV/AIDS. PIs may also have a role in premature aging in HIV/AIDS as they cause prelamin A accumulation. Overall, toxic side effects of HAART may both resemble and promote events of aging and are worthy of mechanistic studies.
IAS: Slowing the premature aging process: the benefits of viral control and smoking cessation on telomere length - (07/27/17)
CROI: Impact of antiretroviral treatment containing tenofovir difumarate on the telomere length of aviremic HIV-infected patients / NRTIs, HIV & Telomerase, Aging, Comorbidities - (03/02/17)
Inhibition of Telomerase Activity by Human Immunodeficiency Virus (HIV) Nucleos(t)ide Reverse Transcriptase Inhibitors: A Potential Factor Contributing to HIV-Associated Accelerated Aging - (01/20/17)
Telomere length: neurocognitive biomarker in HIV-1-infected subjects - (03/02/17)
Leukocyte Telomere Attrition is Rapid Following HIV but not HCV Seroconversion - (03/02/17)
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ABSTRACT & COMMENTARY
Inhibition of Telomerase Activity by NRTI's may Contribute to Accelerated Aging in HIV Patients
June 1, 2013
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.
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