Towards an HIV Cure: New Strategies for an Old Challenge
This session aimed at presenting novel strategies being explored to address the challenge of HIV persistence under antiretroviral therapy and find a solution to control HIV reservoirs in order to achieve at least a functional cure to HIV infection.
From 2011 IAS Conference: Towards an HIV Cure, New Strategies for an Old Challenge
First Nicolas Chomont presented a summary of the Saturday pre-conference workshop on HIV pathogenesis, that we already reported on this site.
Nicolas focused on the talks that were given on HIV reservoirs and HIV persistence.
The first question was about the sensitivity of the tools we have to measure the reservoir. A huge debate is about the existence of ongoing replication on ART. There is a need to explore tissues beyond blood and study if drugs penetrating correctly in tissues can affect residual viremia.
There are ways to activate HIV in latently infected T cells, like with SAHA. It is expected that once activated, these cells will be killed by the virus or by the immune system. We can also target the cell, in particular PD-1. The role of IL-7 remains unclear regarding the reservoir.
The second talk of the session was given by Carine Van Lint on the molecular control of HIV-1 post integration latency. The provirus is blocked at the level of transcription. There are different important factors:
-The site of integration in the host cell genome;
-The absence of inducible cellular transcription factors like NF-KB;
-The chromatin organization and the epigenic control of the promoter; HDAC inhibitors can act at this level.
There is a synergic activity of HDACi and Prostatin or SAHA. But in vitro it is insufficient to induce 100% of the reservoir. Histone methylation is also involved in HIV latency. Chaetocin, an histone methylation inhibitor, has been shown in 5/18 of PBCs from patients to reactivate HIV. DNA methylation is also involved in latency. 5-AZA inhibits this methylation and is synergic in vitro with SAHA
-The absence of Tat and the sequestration of P-TEFb. HMBA is able to release P-TEFb and is also synergic with Prostratin.
In conclusion, there are multiple targets for a purge.
Daria Hazuda from Merck talked about drug development for HIV cure. She renamed her talk as "A game of hide and sleep". Actually, the HIV reservoir is both very stable and quite dynamic. Multiple studies show that raltegravir intensification does not affect residual viremia. It remains to be known if something happens in tissues. The diffusion of ARVs in tissues and fluids is an important concept for developping a cure, to hit the virus where it is hidding. At Merck the "shock and kill" approach is particularly studied. The goal is to identify small molecules able to revert latency. This needs appropriate models of HIV latency. The gold standard is using PBMCs from infected patients but this is not easy for drug screening. The problem is that "constructed" in vitro cellular models do not currently recap all the mechanisms of latency. Merck is using one model where HDACi recativate HIV. They have currently identified 83 potential compounds to reactivate HIV.
The last question is if induction will lead to eradication? Probably eradication will require multiple approaches in combination, including immunological approaches and negative regulators like anti PD-1. Animal models should be used to test these strategies but they are not perfect.
Monsef Benkirane presented his work on HIV persistence and innate immunity. HIV persistence in latently infected cells is also post transcriptionnal. P-TEFb is probably one common limiting step in the process. We need to avoid the block at the elongation level.
Active P-TEFb is a complex more complicated that we initially thought. Negative Elongation Factor (NELF) is another complex that is currently analyzed by Benkirane group, because it has a role too.
The last part of the talk was about the role of mechanisms helping HIV to escape the innate immune response and establish a persistent infection. Instead of playing their role as initiating anti HIV immunity, dendritic cells help disseminating HIV. Vpx is able to make dendritic cells susceptible to productive HIV infection. Benkirane group recently identified the protein SAMHD1 which is involved in this phenomenon, as Vpx produces proteasomal degradation of SAMHD1. It is a restriction factor very different from others. We do not know why HIV-1 did not develop a mechanism to overcome SAMHD1 like HIV-2 did with Vpx.
Joe Wong finally talked about tools for measuring the reservoir and translational research. Total HIV DNA is one reliable tool to measure the reservoir, although not perfect. We can measure by different ways integrated forms of HIV DNA but the assays are more cumbersome and less sensitive. It also still do not distinguish between replication competent and defective viruses. 2LTR circles are a marker for ongoing replication. Cell-associated infectivity remains the gold standard for measuring the reservoir. Cell-associated HIV RNA decays over time but frequently remains detectable. Less adherent patients tend to have higher frequencies of cell-associated HIV RNA even when plasma viremia is <50 copies/ml. Blood contains only 2% of CD4, gut contains about 60% and the lymphatic system contains the rest. So, it is important to look beyond blood.
Key words: HIV eradication, HIV persistence, HIV reservoirs, IAS HIV Cure, IAS conference, towards HIV cure