Digging Into a 039Black Hole039 of HIV Research

A study presented at the recent annual Conference on Retroviruses and Opportunistic Infections (CROI) examined a population of approximately 70 ART-suppressed HIV-infected individuals, in an attempt to find potential new biomarkers and, eventually, new pharmacological targets.

In this exclusive MedPage Today video, Satish Pillai, PhD, of the University of California San Francisco, and Wim Trypsteen, PhD, of Ghent University in Belgium, discuss the methodology and outcomes of their research.

Following is a transcript of their remarks:

Pillai: There are two main outcomes of the research. One of the big kind of black holes in HIV research at this stage is we're trying to understand what mechanisms in the host maintain the HIV reservoir. We're also looking for very simple ways to measure the HIV reservoir since ultimately that's the main obstacle to a cure. We need more efficient and effective ways to measure how our curative interventions affect the size of the reservoir.

Really, what we've learned by surveying this population of approximately 70 HIV-infected individuals is there are really just a small handful of genes whose expression levels are associated with the size of the latent reservoir. There are two things we can do with that. One is those provide potential new biomarkers. One possibility would be that we could measure the expression levels of those genes after a curative intervention, and if they change substantially, that would give us a decent indication that the size of the reservoir has evolved.

The other thing that we're really hoping for, more than just a passive biomarker, we're really hoping that these genes represent new pharmacological targets. For instance, Wim was mentioning the PD-1 gene, the actual gene and coding the PD-1 protein, it may be possible that we could manipulate that pathway pharmacologically to accelerate the eradication of the HIV reservoir. Those are kind of the two main directions that we're going.

Trypsteen: The plan was to look at the CD4 T-cell transcriptome, so the reservoir of HIV-1, and really pinpoint which genes are linked to HIV markers, like HIV-1 RNA/DNA. Interestingly, we could actually pick up gene signatures that are linked to HIV DNA, and the biggest hit there was PD-1, which is a marker for T-cell exhaustion, so meaning that the bigger the HIV reservoir you have, the more PD-1 expression you have. That's for HIV DNA.

If you then look into HIV RNA, the signal is a little bit bigger. We're talking about a couple of genes, but really 140 genes that really behave in the same way as HIV RNA did across 70 HIV-1-infected individuals. The signals there were signal pathways like RIG-I, T-cell exhaustion once more, really proving that what is now being done in the cure field is really what we see at the transcriptome level. Next to that are all of the new pathways that we can actually look at like NOTCH-1, which is not being described yet, but it could be a new adventure, new pathway to dig in and try to find new medicine.

Pillai: Now that we have these gene expression signatures our lab uses gene editing approaches. We use the CRISPR-Cas9 system to specifically manipulate genes of interest. We've already started taking some of the hits from this profiling experiment, and we started mutating them and manipulating them, in vitro models of HIV latency. We've already graduated to the next step, and we're already seeing kind of promising tidbits that some of the hits that we observed in this study do have a meaningful impact on HIV persistence in some models. Really, where we go after that, if we can see that some of these hits really do something interesting in a model in a petri dish, then we're hoping that we'll be able to design new therapies, essentially. That's the more long-range goal.

Scientists Identify HIVs Hiding Place Countdown

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