Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension

Lewis, Mark G.; DaFonseca, Sandrina; Chomont, Nicolas; Palamara, Anna Teresa; Tardugno, Maria; Mai, Antonello; Collins, Matt; Wagner, Wendeline; Yalley-Ogunro, Jake; Greenhouse, Jack; Chirullo, Barbara; Norelli, Sandro; Garaci, Enrico; Savarino, Andrea

doi:10.1097/qad.0b013e328347bd77

Cited by 84 publications

(118 citation statements)

References 44 publications

Supporting

Mentioning

106

Contrasting

Unclassified

Order By: Relevance

“…The mechanism of action of auranofin and BSO is likely three-fold (Figures 2 and 3). First, auranofin causes a reduction in the viral reservoir as a direct consequence of the proapoptotic and prodifferentiating effects of auranofin on memory T cells (26,27) harboring the bulk of latent virus (ref. 104 and Figure 2).…”

Section: Treating Hiv/aids By Increasing Oxidative Stress: Results Frmentioning

confidence: 99%

“…Trx upregulation is observed in murine splenic B lymphocytes following the initial oxidative burst (24). Conversely, inhibition of the Trx system impairs the mitogenic response of mouse splenocytes (25), favors ASK1-mediated cell death of CD4 + T lymphocytes (26), and downregulates costimulatory CD27 and CD28 molecules in T cells (26,27). The GSH system is also necessary for efficient lymphocyte proliferation.…”

Section: The Trx and Gsh Systems In Cancermentioning

confidence: 99%

See 1 more Smart Citation

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

Benhar¹,

Shytaj²,

Stamler³

et al. 2016

Journal of Clinical Investigation

Self Cite

144

115

View full text Add to dashboard Cite

Section: Treating Hiv/aids By Increasing Oxidative Stress: Results Frmentioning

confidence: 99%

Section: The Trx and Gsh Systems In Cancermentioning

confidence: 99%

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

Benhar¹,

Shytaj²,

Stamler³

et al. 2016

Journal of Clinical Investigation

Self Cite

144

115

View full text Add to dashboard Cite

“…Currently, there is a great need for an animal model of HAART in which virus eradication strategies can be explored. Achieving suppression of SIV replication to an extent comparable to that seen in HIV-1-infected humans on HAART is the critical first step in the development of models for viral eradication strategies (12,26). However, it is still not clear what regimen is optimal for suppressing SIV replication in vivo.…”

mentioning

confidence: 99%

A Quantitative Measurement of Antiviral Activity of Anti-Human Immunodeficiency Virus Type 1 Drugs against Simian Immunodeficiency Virus Infection: Dose-Response Curve Slope Strongly Influences Class-Specific Inhibitory Potential

Deng

Zink

Clements

et al. 2012

J Virol

View full text Add to dashboard Cite

cSimian immunodeficiency virus (SIV) infection in macaques is so far the best animal model for human immunodeficiency virus type 1 (HIV-1) studies, but suppressing viral replication in infected animals remains challenging. Using a novel single-round infectivity assay, we quantitated the antiviral activities of antiretroviral drugs against SIV. Our results emphasize the importance of the dose-response curve slope in determining the inhibitory potential of antiretroviral drugs and provide useful information for regimen selection in treating SIV-infected animals in models of therapy and virus eradication.

show abstract

“…Controlled studies in monkeys infected with simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) and anecdotal reports on human immunodeficiency virus type 1 (HIV-1)-infected humans, such as the "Boston patients" and the "Mississippi baby," have shown that reduction of the viral reservoir, or inhibition of its formation, is a crucial factor for controlling viral load in the absence of antiretroviral therapy (ART) but is not its only determinant (3)(4)(5)(6). These reports suggest that without complete eradication of the viral reservoir, viral load control in the absence of therapy is transient or incomplete.…”

mentioning

confidence: 99%

Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection

Shytaj

Nickel

Arts

et al. 2015

J Virol

Self Cite

View full text Add to dashboard Cite

Off-therapy control of viremia by HIV-infected individuals has been associated with two likely players: a restricted viral reservoir and an efficient cell-mediated immune response. We previously showed that a combination of highly suppressive antiretroviral therapy and two experimental drugs, i.e., auranofin and buthionine sulfoximine, was able to reduce the viral reservoir, elicit efficient cell-mediated antiviral responses, and induce intermittent posttherapy viral load control in chronically SIVmac251-infected macaques. We here show that the macaques that had received this drug combination and then stopped antiretroviral therapy were also able to maintain low numbers of activated CD4؉ T cells at viral rebound. Moreover, these macaques consistently displayed low-level simian immunodeficiency virus (SIV) diversity, which was in line with the strong and broadly reactive cell-mediated immune responses against conserved Gag antigens. Extended follow-up showed that the two macaques that had received the complete drug combination remained healthy and did not develop AIDS in 2 years of follow-up after therapy suspension. This disease-free survival is longer than twice the average time of progression to AIDS in SIVmac251-infected rhesus macaques. These results suggest that limited numbers of activated T cells at viral rebound and subsequent development of broadly reactive cell-mediated responses may be interrelated in reducing the viral reservoir. IMPORTANCE The HIV reservoir in CD4؉ T cells represents one main obstacle to HIV eradication. Recent studies, however, show that a drastic reduction of this reservoir is insufficient for inducing a functional cure of AIDS. In the present work, we thoroughly studied and subjected to long-term follow-up two macaques showing intermittent control of the virus following suspension of antiretroviral therapy plus an experimental antireservoir treatment, i.e., the gold salt auranofin and the investigational chemotherapeutic agent buthionione sulfoximine (BSO). We found that these drugs were able to decrease the number of activated CD4 ؉ T cells, which are preferential targets for HIV infection. Then, efficient immune responses against the virus were developed in the macaques, which remained healthy during 2 years of follow-up. This result may furnish another building block for future attempts to cure HIV/AIDS.

show abstract

Gold drug auranofin restricts the viral reservoir in the monkey AIDS model and induces containment of viral load following ART suspension

Abstract: These findings represent a first step towards a remission of primate lentiviral infections.

Cited by 84 publications

References 44 publications

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

A Quantitative Measurement of Antiviral Activity of Anti-Human Immunodeficiency Virus Type 1 Drugs against Simian Immunodeficiency Virus Infection: Dose-Response Curve Slope Strongly Influences Class-Specific Inhibitory Potential

Two-Year Follow-Up of Macaques Developing Intermittent Control of the Human Immunodeficiency Virus Homolog Simian Immunodeficiency Virus SIVmac251 in the Chronic Phase of Infection

Contact Info

Product

Resources

About