Statins Blunt HAART-Induced CD4 T-Cell Gains but Have No Long-Term Effect on Virologic Response to HAART

Rodrı́guez, Benigno; Valdez, Hernán; Mijch, Anne M; Watson, Kerrie; Lederman, Michael M.; McComsey, Grace A.; Loupa, Chariclia; Woolley, Ian

doi:10.1177/1545109707300684

Cited by 12 publications

(11 citation statements)

References 22 publications

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“…However, sustained and co-expression of inhibitory receptors are hallmarks of exhausted T cells, which are prominent in chronic viral infections and cancer [ 2 , 3 , 32 ]. The use of statins as preventive and prophylactic measures for cancer therapy have been proposed [ 51 – 54 ] In addition, statins and other lipid-lowering drugs are administered to HIV patients to avert coronary heart disease [ 55 , 56 ]. In these studies reduction in percentages of TIM-3 and PD-1 by T cells in response to atorvastatin treatment have been reported [ 18 , 25 ].…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling

Okoye

Namdar

et al. 2017

Oncotarget

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Regulation of T cell function in the steady state is mediated by co-inhibitory receptors or immune checkpoints such as PD-1, CTLA-4, TIM-3 and LAG-3. Persistent antigen stimulation, during chronic viral infections and cancer, results in sustained expression of multiple co-inhibitory receptors and subsequently poor effector T cell function. Immune checkpoint blockade using monoclonal antibodies against PD-1, PDL-1 and CTLA-4 has been implemented as an immunotherapy strategy- resulting in restoration of T cell function and reduction of viral load or tumour growth. Immunomodulatory roles of commonly used cholesterol-lowering medications, atorvastatin and other statins, are widely documented. We have previously shown that atorvastatin can inhibit HIV-1 infection and replication. Here, for the very first time we discovered that atorvastatin also regulates activated T cell function by mediating downregulation of multiple co-inhibitory receptors, which corresponded with increased IL-2 production by stimulated T cells. In addition, we found that atorvastatin treatment reduces expression of mTOR and downstream T cell effector genes. We demonstrate a novel mechanism showing that atorvastatin inhibition of Ras-activated MAPK and PI3K-Akt pathways, and subsequent mTOR signalling promotes gross downregulation of co-inhibitory receptors. Thus, our results suggest that statins may hold particular promise in reinvigorating T cell function in chronic conditions.

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Section: Discussionmentioning

confidence: 99%

Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling

Okoye

Namdar

et al. 2017

Oncotarget

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“…In addition, laboratory studies have suggested that statins may inhibit HIV viral replication [31–33]. However, the effect of statin on HIV RNA level in humans has not been consistently demonstrated [30,34]. …”

Section: Discussionmentioning

confidence: 99%

HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons

Chao

Abrams

et al. 2011

Aids

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Objective Experimental studies suggested that HMG-CoA reductase inhibitors (‘statins’) may have antilymphoma properties. We investigated whether statin use is associated with reduced risk of non-Hodgkin lymphoma (NHL) in HIV-positive persons. Design A nested case–control study was conducted among HIV-positive members of Kaiser Permanente California, a large managed care organization. Methods Cases were incident HIV+NHL diagnosed from 1996 to 2008. Controls were HIV-positive members without NHL matched 5 : 1 to cases by age, sex, race, index year and known duration of HIV infection. Data were collected from Kaiser Permanente’s electronic medical records. Conditional logistic regression was used to examine the effect of statin use on HIV+NHL risk, adjusting for potential confounders (matching factors, prior clinical AIDS diagnosis, antiretroviral use, baseline CD4 cell count, and history of selected co-morbidity) and use of nonstatin lipid-lowering therapy (LLT). Results A total of 259 cases and 1295 controls were included. Eight percent of the cases and 14% of the controls had a history of statin use. Statin use was associated with lower risk of HIV+NHL; hazard ratio and 95% confidence intervals for ever use, less than 12, and at least 12 months cumulative use was 0.55 (0.31–0.95), 0.64 (0.31–1.28), and 0.50 (0.23–1.10), respectively. P value for trend for duration of statin use was 0.08. No association between nonstatin LLT use and risk of NHL was observed. Conclusion Our results suggested an inverse association between statin use and risk of NHL in HIV-positive persons. Potential limitations include the likelihood of residual confounding by indication and limited study power for some statin use subgroups.

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“…In addition, in small retrospective cohort studies, the data suggested that the use of statins was associated with lower CD4+ T cell responses in patients on HAART [70, 71]. In contrast, however, randomized controlled trials have not observed any changes in CD4 counts with statin therapy [54•, 72].…”

Section: Implications Of Immunological Effects Of Statins In the Hiv-mentioning

confidence: 99%

“…In contrast, however, randomized controlled trials have not observed any changes in CD4 counts with statin therapy [54•, 72]. Similarly, a number of studies have shown in vitro HIV inhibition with statins [73–77], but this has not played out in vivo [53, 71, 72]. …”

Section: Implications Of Immunological Effects Of Statins In the Hiv-mentioning

confidence: 99%

The Role of Statins in the Setting of HIV Infection

Eckard

McComsey

2015

Curr HIV/AIDS Rep

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HIV-infected individuals are at an increased risk of cardiovascular disease (CVD) and other HIV-related co-morbidities. This is due in part to dyslipidemia associated with antiretroviral therapy and increased inflammation and immune activation from chronic HIV infection. Statins not only have potent lipid-lowering properties but are also anti-inflammatory and immunomodulators. Studies suggest that statin therapy in the HIV-infected population may decrease the risk of CVD and other non-AIDS-defining co-morbidities. This review summarizes the recent literature on statin use in the HIV setting.

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Statins Blunt HAART-Induced CD4 T-Cell Gains but Have No Long-Term Effect on Virologic Response to HAART

Cited by 12 publications

References 22 publications

Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling

Atorvastatin downregulates co-inhibitory receptor expression by targeting Ras-activated mTOR signalling

HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons

The Role of Statins in the Setting of HIV Infection

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