AIDS cure? Nature Didn't Say That!

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Healing of AIDS The AIDS Pandemic

Healing of AIDSHealing AIDS! Um sonho para muitos! E que venha logo. Mas que venha corretamente! Não como promessas alegadamente alvissareiras e só…

Mara gave me a warning about a subject and I went hunting for the study.

And I found it. It uses the terminology shock and death that reminds me of another pharmacopoeia of scientists:

The so-called “kick and kill”. Many kicks later nothing was dead. Except for my almost unlikely hopes! Yes! I had a lot of hope at the time and, given the results then, I now have some hope.

The cure for AIDS is not something for today. We have a lot to solve

Nothing like moderation.

Because, as it is in nature, ‘choque e morte’ pode parecer nome de estratégia militar, mas, na verdade, descreve o modelo dominante atualmente used in the search for a cure for infection by HIV-1 which, a short time ago, I reinforce, was to kick and kill.

Although antiretroviral therapy (ART) is highly effective in limiting the extent of infection, the virus can hide “latente” in immune cells called CD4 cells+ T, in reservoirs.

And most of these reservoirs remain in the cells that make up the intestinal tubes, which, open and spread, occupy nothing more, nothing less, than the proportions of an official football field, undergoing little or no transcription and, therefore, undetectable by immune system 1,2.

AZD5582 😡not optimized for use on humans 😡; however, these results suggest that pharmacological activation of the non-canonical NF-κB pathway may be an attractive way to trigger the expression of the HIV-1 gene as part of a shock and death approach (Fig. 1).

I do not have permission to publish the image - At the end of the text I will put the writings related to the image 

Although antiretroviral therapy (ART) is highly effective in limiting the extent of infection, the virus can hide “latente” in immune cells called CD4 cells+ T, in reservoirs.

And most of these reservoirs remain in the cells that make up the intestinal tubes, which, open and spread, occupy nothing more, nothing less, than the proportions of an official football field, undergoing little or no transcription and, therefore, undetectable by immune system 1,2.

Healing of AIDS

Very Calm At This Time HIV Cure Certainly Delays

The problem itself is the need to make sure of these shorts,

And she is a sensible woman, virologist of University of Paris P It all started in 1983, when the researcher published in the journal Science the description of a retrovirus that would later be called HIV. The scientist, years later, recognized that at that time they were very naive. The link opens in another tab!

CLEARLY INSUFFICIENT

Much work remains to be done

The fact is that Ronald Reagan has promised a vaccine and an AIDS cure for two years from now and, not quite thirty years later, not much is known.

E, colando uma amiga e infectologista “a AIDS é a pontinha do iceberg de tudo o que acontece em nossos corpos depois do HIV entrar nele

Tais tratamentos ainda precisam ser projetados.(…)

😡 And our media comes talking about healing😡

I received a message from a friend a few hours ago:

HIV cure? AIDS cure
A intenção dele é boa e eu sou grato pelos votos. Mas a percepção dele está equivocada pela forma com as quais as notícias são colocadas! (…_

In the second study, McBrien et al4 used a completely different, though complementary, approach to stop viral latency. Again, the authors used humanized mice ART-treated after HIV-1-infected and SIV-infected rhesus monkeys treated with ART.

It will not be with an isolated immunological intervention

They combined two immunological interventions. The first involves antibody-mediated depletion of CD8 cells+ T- immune cells previously demonstrated in action in conjunction with HAART to reduce levels of viral transcription5.


The second, administered concomitantly, involves treatment with a drug called N-803, which strongly activates the signaling molecule interleukin-15 (IL-15), and which was previously shown 6 to activate HIV-1 transcription vitro. Like Nixon and colleagues, the researchers found that their treatment caused substantial increases in virus levels in the blood and viral RNA in cells of various tissues.

Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8 + cells

I cannot use the figure due to unreleased copyrights but the caption for figure one says what follows below

Figure 1 Two approaches to reactivate sleeping HIV-1. HIV-1 can integrate into the genome of latent CD4 + T cells - it is not transcribed into messenger RNA and, therefore, is not detected by the body's immune system. Two articles describe "shock" treatments that can reactivate the transcription of latent HIV in mice and the related SIV virus in monkeys. Nixon et al.3 used a drug called AZD5582 to activate the non-canonical NF-κB signaling pathway, which stimulates virus transcription. McBrien et al.4 used two interventions - a drug called N-803 to stimulate the IL-15 protein, which promotes transcription, and an antibody treatment that depletes immune cells called CD8 + T cells, which appear to play an important role in decreasing HIV transcription. After these shock treatments reactivated the virus, interventions that target and kill CD4 cells carrying viruses, TK cells should help eliminate the latent viral reservoir. 

At first glance, the combined interventions used by McBrien and colleagues may seem contradictory, because IL-15 is one of the strongest activators of CD8 + T cells7,8. Mas os efeitos sinérgicos dessas duas intervenções levantam a possibilidade provocativa de que as melhores estratégias para atingir células reservatórias virais envolvam uma mistura de intervenções imunes – suprimindo componentes imunes que parecem ter um papel na estabilização da latência viral (como as células CD8+ T) enquanto ativa outras que podem interromper efetivamente a latência (como a sinalização de IL-15).

And the Original Text says this:

How exactly CD8 + T-cell depletion interacts with IL-15 to reverse HIV-1 latency is unknown.

It is not known exactly how CD8 + TR interacts with IL-15 to reverse the latency of HIV-1.


When someone writes something like this, anyone with a good interpretation of the text realizes that there is no talk of a cure for today or tomorrow !!!! Am I wrong ^?

It's something like that! I can't understand how a scientific text can yield what it made as a headline in this country's media !!!!!

Given the wide range of direct and indirect effects resulting from CD8 cell depletion+ T9, it will not be easy to define the precise molecular mechanisms underlying this synergy. However, understanding this relationship can reveal the proteins that are targeted together by these interventions and, therefore, could be used to optimize the reversal of latency in the clinic.

In addition to the advances they make, current studies show some of the conceptual and technical challenges inherently associated with reversing pharmacological latency.

First, the latency reversal agents (LRAs) evaluated (as well as all other LRAs described so far 10) target factors that play a crucial role in modulating the transcription of host cell genes (ours), in addition to viral transcription.

Its use, therefore, carries an intrinsic risk of toxic effects outside the target.

Lethal Defects and Uncertainties

The toxicity of the LRAs described by McBrien et al. and Nixon et al. appears to be acceptable in animal models, with the majority showing no clinical side effects. However, much stricter safety standards must be met in clinical trials in humans. (Ufa)!

Lethal Defects

Viral latency mechanisms can vary between individual viral reservoir cells and are probably influenced by the position in which HIV-1 genomes have integrated with host cell chromosomes 11. Therefore, it is possible that only subsets of cells respond to individual LRAs, which gerally target a specific viral latency mechanism. The actual proportion of cells in the viral reservoir that responded to interventions in the two current studies is uncertain and would be difficult to determine experimentally 12.

Another uncertainty is how much of the increase in HIV-1 RNA is attributable to CD4 cells+ HIV-1 carriers that can replicate effectively 13,14.

This is interesting because most of the viral reservoir cells harbor HIV-1 genomes that contain lethal defects in the sequence, probably as a result of errors introduced during the reverse transcription of viral RNA, that produces viral DNA that is integrated into the host genome.

Stuns But Doesn't Kill

These defective viral genomes can often still be transcribed and respond to local and regional authorities, but they cannot cause viral rebound when ART is stopped and, therefore, do not represent the main target of shock and death interventions.

Além disso, não está claro como a latência perturbadora pode influenciar a dinâmica evolutiva das células do reservatório – se, por exemplo, um tratamento de choque mata alguns subconjuntos de célula sCD4+T that are highly susceptible to interruption of latency, but gives a selective advantage to other subsets of cells that are not susceptible and difficult to reactivate.

Most importantly, none of the interventions tested in the current studies led to a change in the expression of markers of the size of the viral reservoir.

A decrease in these markers is the most informative and crucial endpoint for addressinggens de choque e morte. A ausência de um efeito no tamanho do reservatório viral provavelmente reflete o fato de que os estudos foram projetados principalmente para investigar a reversão da latência e careceram de intervenções dedicadas de “morte”.

Important step in the search for Healing? Yes! But it is not Healing! And there's a long way

Na Busca pela Cura, combinar intervenções de “choque” com componentes de “morte” é um próximo passo importante.

De fato, o fato de fornecerem um modelo adequado para avaliar estratégias de ‘morte’ no cenário de reversão de latência robusta e eficiente pode ser um dos pontos fortes dos estudos atuais.

Healing of AIDS

Finally, the work of Nixon and colleagues and McBrien and colleagues should not be distracted from the fact that the shock and death strategy still largely remains a theoretical concept, not a therapeutic reality.

Nature still reinforces

Establishing evidence of its ability to reduce viral reservoirs and offer real benefits to patients will require much more work. doi: 10.1038 / d41586-020-00010-x

Translated by Claudio Souza's original Reactivation of latent HIV moves shock-and-kill treatments forward

References

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    2. Alleys, DS & Greene, WC Cell 155, 519-529 (2013).

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    2. Nixon, CC et al. Nature https://doi.org/10.1038/s41586-020-1951-3 (2020).

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    2. McBrien, JB et al. Nature https://doi.org/10.1038/s41586-020-1946-0 (2020).

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    2. Cartwright, EK et al. Immunity 45, 656–668 (2016).

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    2. Jones, RB et al. PLoS Pathog. 12, e1005545 (2016).

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    2. Conlon, KC et al. J. Clin. Oncol. 33, 74-82 (2015).

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    2. Younes, S.-A. et al. J. Clin. Invest. 126, 2745-2756 (2016).

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    2. Okoye, A. et al. J. Exp. Med. 206, 1575-1588 (2009).

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    2. Spivak, AM & Planelles, V. Annu. Rev. Med. 69, 421-436 (2018).

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    2. Chen, H.-C., Martinez, JP, Zorita, E., Meyerhans, A. & Filion, GJ Nature Struct. Mol. Biol. 24, 47-54 (2017).

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    2. Cillo, AR et al. Proc. Natl Acad. Sci. USA 111, 7078–7083 (2014).

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    2. Ho, Y.-C. et al. Cell 155, 540–551 (2013).

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    2. Lee, GQ et al. J. Clin. Invest. 127, 2689–2696 (2017).

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