HIV Cure: Controversy, Consensus, and a Consortium

Johnston, Rowena

doi:10.1089/aid.2010.0087

Cited by 5 publications

(4 citation statements)

References 23 publications

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“…Despite undetectable viral load in patients treated with potent antiretroviral therapy, proviral genomes remain in the latent reservoirs rendering the total clearance of HIV an unattainable goal at present (Finzi et al, 1997; Pierson et al, 2000; Yang et al, 2009). Hence, the search for a cure is one of the most challenging and rewarding areas of HIV/AIDS research (Geeraert et al, 2008; Johnston, 2010). …”

Section: Introductionmentioning

confidence: 99%

Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

et al. 2014

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The ability of HIV to establish long-lived latent infection is mainly due to transcriptional silencing of viral genome in resting memory T lymphocytes. Here, we show that new semi-synthetic ingenol esters reactivate latent HIV reservoirs. Amongst the tested compounds, 3-caproyl-ingenol (ING B) was more potent in reactivating latent HIV than known activators such as SAHA, ingenol 3,20-dibenzoate, TNF-α, PMA and HMBA. ING B activated PKC isoforms followed by NF-κB nuclear translocation. As virus reactivation is dependent on intact NF-κB binding sites in the LTR promoter region ING B, we have shown that. ING B was able to reactivate virus transcription in primary HIV-infected resting cells up to 12 fold and up to 25 fold in combination with SAHA. Additionally, ING B promoted up-regulation of P-TEFb subunits CDK9/Cyclin T1. The role of ING B on promoting both transcription initiation and elongation makes this compound a strong candidate for an anti-HIV latency drug combined with suppressive HAART.

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Section: Introductionmentioning

confidence: 99%

Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

et al. 2014

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“…M any viruses exhibit a high mutation rate when replicating their genomes, enabling quick adaptation to both changing cellular environments and therapeutics (1)(2)(3)(4)(5). Mammalian innate immune systems have developed a mechanism to exploit this high mutation rate against the virus; in a phenomenon termed "lethal mutagenesis," (6)(7)(8)(9)(10)(11)(12)(13)(14) the immune system employs nucleic acid-modifying enzymes (e.g., APOBEC and ADAR) to increase the viral mutation rate sharply, stressing the functional gene product repertoire of the virus to the point that the viral population collapses (15)(16)(17).…”

mentioning

confidence: 99%

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

Fedeles

Singh

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Unlike conventional antiviral therapy, lethal mutagenesis is a therapeutic strategy that exploits the high mutation rates of certain viruses. It works by intentionally increasing the viral mutation rate, causing excessive error accumulation and viral population collapse. The mutagenic nucleoside analog 5-aza-5,6-dihydro-2′-deoxycytidine (KP1212) is specifically designed to use lethal mutagenesis against HIV. The mechanism of KP1212 mutagenesis was proposed to involve tautomerism—the repositioning of active protons on the nucleic acid base on a fast time scale. Using a multifaceted approach, we demonstrate that KP1212 exists in multiple tautomeric forms, and that the tautomeric distribution correlates with the mutagenic properties of KP1212. This work also provides a toolset for studying tautomerism in nucleic acids and developing the next-generation antiviral lethal mutagens.

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“…5 Due to its ability to replicate and suffer mutations excessively and close to the error threshold, HIV-1 currently remains as a treatable but incurable infection. 6 Following their original description, the apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3 family (APOBEC3s) is composed of the first enzymes described whose catalytic activity interferes with viral replication by leading HIV-1 viral populations into an error catastrophe. 7 Hypermutation is detected in HIV-1 as a monotonous accumulation of guanine-to-adenine (G/A) substitutions along the virus genome.…”

Section: Introductionmentioning

confidence: 99%

In VivoHIV-1 Hypermutation and Viral Loads Among Antiretroviral-Naive Brazilian Patients

Lima-Stein

Alkmim²,

Bizinoto³

et al. 2014

AIDS Research and Human Retroviruses

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Hypermutation alludes to an excessive number of specific guanine-to-adenine (G- >A) substitutions in proviral DNA and this phenomenon is attributed to the catalytic activity of cellular APOBECs. Population studies relating hypermutation and the progression of infection by human immunodeficiency virus type 1 (HIV-1) have been performed to elucidate the effect of hypermutation on the natural course of HIV-1 infection. However, the many different approaches employed to assess hypermutation in nucleotide sequences render the comparison of results difficult. This study selected 157 treatment-naive patients and sought to correlate the hypermutation level of the proviral sequences in clinical samples with demographic variables, HIV-1 RNA viral load, and the level of CD4(+) T cells. Nested touchdown polymerase chain reaction (PCR) was performed with specific primers to detect hypermutation in the region of HIV-1 integrase, and the amplified sequences were run in agarose gels with HA-Yellow. The analysis of gel migration patterns using the k-means clustering method was validated by its agreement with the results obtained with the software Hypermut. Hypermutation was found in 31.2% of the investigated samples, and a correlation was observed between higher hypermutation levels and higher viral load levels. These findings suggest a high frequency of hypermutation detection in a Brazilian cohort, which can reflect a particular characteristic of this population, but also can result from the method approach by aiming at hypermutation-sensitive sites. Furthermore, we found that hypermutation events are pervasive during HIV-1 infection as a consequence of high viral replication, reflecting its role during disease progression.

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HIV Cure: Controversy, Consensus, and a Consortium

Cited by 5 publications

References 23 publications

Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

Reactivation of latent HIV-1 by new semi-synthetic ingenol esters

Tautomerism provides a molecular explanation for the mutagenic properties of the anti-HIV nucleoside 5-aza-5,6-dihydro-2′-deoxycytidine

In VivoHIV-1 Hypermutation and Viral Loads Among Antiretroviral-Naive Brazilian Patients

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