ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

Most cells infected with HIV are CD4's- what makes these cells persist long term.?

CD4cells have attributes of expanded cellular clones. The larger the cluster the older it is.

In HIV controllers, most are restricted to a particular tissue site.

Infected cells can traffick out into the blood and expand.

Can infected CD4cells capable of producing virus clonally expand in Vivo?

Where does virus replication occur in HIV controllers?Blood and lymphoid tissue are v. Different reservoirs.Rare sequences survived to traffick out of blood and into lymphoid tissue.

Are there any sequence similarities between lymph nodes at different sites?

The reservoir contains an archive of viral evolution

Those interested in the concept of post-treatment controllers and treatment remission, please head to Saez-Cirion's (of Visconti fame) presentation tomorrow (Monday 20 Juyl) at the 11am - persistently seeking virus. I will write a detailed post after the session as this abstract is currently under embargo.

Tagged in: IAS2015

Greetings from Vancouver IAS 2015! Reporting back after Day 1 of the 2-day IAS Cure symposium. 

Our key speakers today included:

  • Dan Kuritzkes who gave a nice overview of the progress and challenges in HIV cure research
  • John Mascola on neutralising antibodies including bispecific (combination) antibodies and the "ideal" antibody - cheaper, longer half life, subcutaneous delivery, more potent, greater breadth. There are two good sessions on neutralising antibodies MOBS03 on 20 July 11am and WESY06 on 22 July for those interested in this topic. Both should be terrific sessions.
  • Marcus Altfeld spoke about immune recognition following latency reversal, and drew on his expertise on NK cells. They have a new nef inhibitor.
  • Matthew Sharp - reminded us to keep the community engaged and also highlighted a great resource CUREiculum http://www.avac.org/cureiculum. Take a look.

We had two "roundtables" today: one on paediatric HIV cure research and the other on combination therapy. There was robust discussion about the need to advance cure research in paediatric children in parallel with adults, but at the same time being sensitive to the issues of risk and acceptability. Some of the most interesting work in HIV cure research is being done in hyper-acute/ very-very early commencement of ART in paediatrics with the aim to reduce the establishment of the latent HIV viral reservoir, +/- in combination with neutralising antibodies +/- structured treatment interruption. Did you know there is an infant monkey model? Well, there is!

Some new ideas presented today included Ingenol a Protein kinase C inhibitor (Planelles), and CD4 mimetics (Finzi), AGS004 a fully autologous DC-based immunotherapy electrophorated with autologous HIV RNA and genetic differences in the reservoir (Karn). 

 

David Evans from Project Inform reminded us on the need to manage the excitement about progress in cure research.

The oral abstracts are under embargo so I cannot detail those here. For those interested in HIV cure research, please follow the road mapHIV Pathogenesis (Molecular Biology - Virology - Reservoirs) found on the IAS website. 

Till next time.

 

Tagged in: IAS2015

“To know your Enemy, you must become your Enemy.” The quote by Sun Tzu perfectly captures the theme of the session titled Defining and Targeting Residual Virus on cART.

And so Dr Keele presented an innovative molecular tag of SIV to help better understand the location, size and variability of persistent SIV infection in non-human primates. The “barcode” approach presented allows multiple viral variants to establish infection and then be identified over the course of disease progression. This will hopefully lead to the researchers tracking down the actively replicating viruses that are responsible for maintaining the reservoir and studying how this morphs once ART is introduced and subsequently ceased. Although non-human primate models seem far removed from the clinic, these models are essential for a better understanding of how and where HIV is hiding in the body.

Much closer to home comes the follow-up of a unique patient known as C135 who was part of the Sydney Blood Bank Cohort (SBBC) and infected with HIV 33 years ago. Infected with an attenuated ∆-nef strain of virus, C135 presented as an elite controller with 3 genetic polymorphisms associated with viral control, including protective HLA class I and HLA class II alleles, and CCR5∆32 heterozygosity – a truly distinct combination when accounting for the attenuated virus. Samples taken 15 years after blood transfusion indicated established HIV-1 infection, but in samples from 1997 onwards infectious HIV-1 has never been recovered from PBMC cultures and no HIV-1 DNA found in CD4+ T cells from either PBMC or gut biopsies. The patient has remained off ART since infection and presents a strong case for either viral clearance or at least sustained virological remission. Unfortunately, the current difficulty of sampling all possible reservoir sites in the body such as the CNS makes confirming viral clearance particularly challenging.

The session concluded with a late breaker from Dr Søgaard from Denmark, who presented the results of a clinical trial to assess the effects of romidepsin (an HDAC inhibitor) on the latent reservoir in 6 HIV-infected patients. The phase I/II clinical trial,  gave six aviremic HIV-infected adults intravenous romidepsin (5 mg/m2) once weekly for 3 weeks while maintaining cART. 36 adverse events were reported although the majority were mild and resolved spontaneously. Viral load increased from undetectable at baseline to readily quantifiable levels at multiple post-infusion timepoints in 5 of 6 patients (range 46-103 copies/mL after 2nd infusion, p=0.007) – the first time this has been seen with an HDAC inhibitor. Furthermore, the emergence of quantifiable plasma HIV-1-RNA corresponded directly with the cyclic romidepsin infusions. However, the HIV-1 RNA levels returned to baseline a few days post infusion and no significant change was detected in total viral DNA across the 6 patients suggesting a transient effect of the drug and no permanent decrease in the size of the viral reservoir. Further trials with larger numbers of patients and/or in conjunction with other therapeutic interventions are eagerly awaited.

 

 

 

 

Tagged in: AIDS 2014 IAS2014

The session gave an overview of viral reservoirs, factors affecting latency and the complexity of latency between and within tissue types.

Dr Persaud from the United States began the session with the unfortunate news and analysis of the re-emergence of HIV infection in the “Mississippi child”. The researchers detected HIV-1 plasma RNA 27 months after earlier assays showed no virus present. Phylogenetic analysis of the virus confirmed it to be a 98% similar to the virus isolated from the mother, strongly suggesting reemergence from “viral remission” rather than the child becoming newly infected via another source.

Dr Van Lint from Belgium then gave a brisk yet detailed overview of viral latency mechanisms. She referenced studies which showed HIV-1 preferentially integrates into transcriptionally active regions of the genome and areas associated with clonal expansion when infecting T-cells.

Dr Van Lint also gave an overview of existing “anti-latency” agents such as vorinostat (SAHA), and newer agents such as Romidepsin, which may be more potent – very much needed if the approach is to be effective in virally suppressed patients on ART.

The presentation was finished with a description of the many cell-associated and viral factors involved in latency and thus the multitude of potential targets for anti-latency therapeutics. However, as research emerges on the complexities of HIV viral latency, it also highlights the heterogeneity of the mechanisms involved in latency within different tissue and cell types and even between individual cells. Any future therapies will need to accommodate this if they are to have any lasting benefit.

Dr Verdin from the United States reiterated the complex nature of viral latency and then described an innovative system using Green Florescent Protein (GFP) and other reporter genes to visualise a profile of genes associated with viral latency (both promoting and suppressing).

This produced a milieu of genes and related protein complexes involved, some known previously, others completely new to the viral latency field. An unexpected outcome of the increased understanding of the breadth of cell-associated factors involved in latency was the closing suggestion of considering therapeutic agents to increase or promote viral latency rather than suppress it (unlike the current experimental agents being trialled which aim to reduce viral latency). By targeting the integrated proviral DNA and “locking it in place”, away from transcription and subsequent virus production, the outcome could be similar to ART, but perhaps more potent?


Dr Chomont from the United States followed on by describing the heterogeneity within latently infected CD4+ T cells and the proportion of subsets infected within different patient groups such as post-treatment controllers and long-term non-progressors.

Both have higher proportions of latently infected cells with a more differentiated phenotype (which have a shorter turn over period within the body). He then described the role of early treatment on latently infected CD4+ T cells with mixed results.

For example Buzon et al. 2014 showed that early ART initiation did not affect the proportion of the more naive (and longer lasting) cells being infected.

However, research discussed by Dr Jintanat Ananworanich earlier in the day suggested that very early initiation of ART (2/3 weeks after infection) was associated with a reduction in the size of the reservoir in all CD4+ T-cell subsets, including the longer lasting central memory cells.

Dr Chomont also remarked that this benefit could remain even if treatment is delayed until 4-8 weeks after infection - still very early initiation within a real world setting however.

The session was concluded by Dr Melissa Churchill, from the Burnet Institute, Melbourne who presented on the role of tissue reservoirs and in particular the CNS. She described the role of the CNS as a probable viral reservoir citing multiple indirect studies, but also acknowledging the lack of conclusive and direct evidence.

Latency in the CNS is likely and, just as was reported in earlier presentations, so is the heterogeneity in latency between the different cell types susceptible to HIV infection in the CNS; astrocytes, macrophages, and microglial cells.

Dr Churchill concluded by discussing the potential role of current curative strategies (such as using histone deacetylase [HDAC] inhibitors) on the CNS with some caution – cell death within the CNS even if targeted specifically to latently infected cells would likely have negative consequences for the tissue and therefore the patient.

Tagged in: AIDS 2014 IAS2014

Please join us for a memorial event celebrating the life of one of Australia’s leading HIV advocates, Levinia Crook… https://t.co/N7dof5xaGa

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