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ASHM CONFERENCE 2017

Undetectable Viral Load Prevents HIV Transmission in Male Serodiscordant Couples in Australia, Thailand and Brazil.

Benjamin Bavington

Monday 6^th

One of the first presentations in the 2017 ASHM conference was the talk that was initially given to the Paris IAS conference in July this year on the final outcomes of the Opposites Attract Study.  This research was unique as its focus was on HIV transmission in HIV discordant male gay couples.  This study showed no linked transmissions between discordant couples where the positive partner had an undetectable viral load.  The researchers took phylogenic ‘finger-prints’ of the positive partners virus at the beginning of the study so if the other person became positive they could determine if it was the same virus.  To be included on the research the gay couple had to attend at least twice per year, the positive person had a viral load, STI check and questionnaire, while the negative partner had an HIV test and STI check plus the questionnaire. The following is just a glimpse of the statistics from the research

·         343 couple were followed

·         2 international sites (Thailand and Brazil), 13 Australian sites for recruitment

·         ~40% in the first year of the relationship – historically there is a larger potential for transmission in this first year compared with longer term relationships

·         75% of the pos people were on ART for the entire study, 25% commenced during the course of the study

·         Of all the positive participants on ART -  75% were fully suppressed, this was due to numbers from the Thai cohort skewing the figures – the Australian cohort had much greater numbers of positive participants being fully suppressed.

·         At the beginning of the study only 7% of negative men were on prep – this grew to 30 % by the end of the research

·         35% of the participants had a STI during the research period

·         In the Australian cohort ~68% reported condomless anal intercourse (CAI) at the beginning of the study and 88.9% by the end. 

·         There were 3 partners who became positive through the project – none of these infections were linked to the positive partner.  All 3 people reported CAI outside of the regular relationship

The conclusion was that with the partner having an undetectable VL there were no linked transmissions.  It is not clear how the role of STI plays in this cohort with regard to transmission of HIV.

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Prof Damian Purcell from the Peter Doherty Institute in Melbourne presented some exciting research in this morning’s Late Breaker session looking at novel HIV latency reversing agents in the pursuit of an HIV cure.  We have heard previously about the ‘shock and kill’ approach to HIV cure, where latently infected cells are stimulated to produce new virus production with the aim of inducing cell death without activation. There have been several clinical trials using a variety of latency reversing agents (LRAs) including the histone deactylase inhibitors (HDACi) vorinostat and romidepsin. However, although these drugs were able to stimulate HIV transcription, they did not reduce the pool of latently infected cells. In addition, these drugs are non-specific and have an effect on all cells, even those uninfected.

Damian spoke of a model developed by his laboratory to target latently infected cells with full-length provirus containing the viral protein Tat. Using a cell line model with various reporters, his team was able to screen a library of drug-like compounds to assess latency reversal that is specific to Tat-containing (i.e. HIV-infected) cells. Multiple ‘hits’ were obtained from the screen, and narrowed down to 1 potential compound that was tested using CD4+ T-cells obtained from virally suppressed patients.  This compound was classed as an amidothiazole and was shown to increase unspliced HIV-RNA in patient-derived CD4+ T-cells ex vivo. It is thought to exert its latency reversing activity through interaction with the methyltranferase complex. This compound was also found to synergise with another class of LRA known as bromodomain inhibitors.

Identification of this this novel compound is exciting as it provides another step towards finding the ideal LRA that could be targeted towards latently infected cells while minimizing effects on uninfected cells. However, there is still further research required to see its efficacy in reversing latency – an important step would be to identify whether this compound actually stimulates production of functional virus (rather than just unspliced RNA). Further research into its safety profile would also be necessary.  

In this presentation by UNSW post-doc fellow Dr Anupriya Aggarwal investigated the role of actin in HIV cell to cell spread. They looked at the structure of actin and the location of HIV in the actin during viral assembly and then budding. HIV was found more often on the curved actin surface versus the shaft area, and intersects with the ARP 2/3 pathway. The presentation was full of amazing 3-D representations of their findings - with the localisation of HIV eGFP shown in relation to the cell surface.

Damian Purcell from the Doherty presented the story of discovery of a new latency reversing agent, currently in the process of in vitro experimentation using ex-vivo patient cells.

Background : agents trialled to reverse latency - PKC activators, HDAC inhibitors, Bromodomain inhibitors 

So why is a novel agent needed? Lack of specificity and potency have been a significant problem in agents to date, many of which have come from the cancer field.

For example - Work from the Purcell/Lewin labs at the Doherty has shown that HDACi inhibit expression of key HIV splicing proteins; HDAC inhibitors in vitro are unable to elucidate expression of spliced RNA, Bromodomain inhibitors on the other hand are able to lead to spliced RNA; this is rescued by the addition of tat protein.

Considering Tat ; 'the master regulator of HIV-1' - (its own latency reversing agent?) by recruiting kinases which help in regulating HIV transcription and RNA processing; Tat itself is also acetylated (thereby activated), which could also be inhibited by HDACi.

So what about new drugs? What do we want?

Tat can be produced without production of virus - and is a neuropathic protein...

Tat induces LTR specific response specifically. This is important, considering that what we are interested in is finding HIV-specific activation pathway 

A drug library was screened to look for agents activating tat in particular - (WEHI) - resulting in an amidothiazole being identified. Medicinal chemistry was used to increase the potency of the compound, which was then trailed on patient derived cells (obtained via leukapheresis); this demonstrated reactivation.

These agents appear to synergise strongly with bromodomain inhibitors (currently trailed agents) and appear to be specific for HIV reactivation, and selective for HIV containing cells that contain tat. 

Minding the Gap - Daryl O'Donnell, CEO AFAO Australia

Spoke of the exciting possibility of ending HIV transmission in Australia. The laying down of a blueprint of this and the potential savings in new infections and healthcare costs in Australia. The challenge of what is needed to achieve this is sobering and important - commitment, money, vision and importantly more research into knowing our epidemic and the strategies that will work in our setting to achieve this. A great step by the government to consider this and be involved. An inspiring vision to work towards.