HIV cure at the 2014 Institute of Human Virology Meeting
The annual meeting of the IHV took place this year in Baltimore, Maryland, 14-17 September 2014.
An entire session on Monday morning was dedicated to HIV cure, HIV reservoirs and HIV latency.
All the renowned researchers of the field were present to give not only a State-of-the-Art of HIV cure issues, but also present new, unpublished data, from their laboratories.
Below you will find a short summary of what was presented.
The issue of HIV cure is now in the frontline.
That is why an entire morning was devoted to this topic.
The first presentation was given by John Mellors. He discussed how the Berlin Patient has been cured. According to recent data published in CID this year (Symonds et al), he had no X4 virus at baseline. However, Mellors confessed that allogenic BMT is not scalable and brings a 7-30% mortality. It was justified in the Berlin patient because he had leukemia.
Mellors also presented data from Kordelas and al. (New England Journal of Medicine 2014) showing that failure of a CCR5- transplant can be due to a shift to X4.
According to Mellors, anti-PD1 and anti-PD1L that were recently approved for cancer immunotherapy (Merck) have a bright future for HIV cure.
Louis Picker presented his model using a CMV vector for a vaccine against SIV. In his hands, the virus was controlled and even disappeared in 50% of the monkeys.
Daniel Kuritzkes recapped the difficulties to see light at the end of the tunnel. In an elegant present presentation he suggested that there is however light in the tunnel but we do not know how long the tunnel is. He emphasized the fact that long-lived tissue reservoirs inaccessible to clinical sampling may contribute to viral rebound at the end.
Robert Siliciano did a review of the huge work done by his lab. In particular he showed that CTL escape mutants are rare at the time of acute HIV infection but represent 100% of viruses later on. He also presented data showing that 12% of proviruses are non mutated and among them 92% are replication competent. To demonstrate that, he used a very time consuming PCR method. Shifting to modelization, Siliciano demonstrated that at least a 3 log reduction of the reservoir would be necessary to get 1 year free from therapy.
Edward Berger presented already published data on immunotoxins and new data on the potential use of chimeric antigen receptors.
In a nice military suit, Jerome Kim presented results during acute HIV infection. The RV254 cohort conducted in Asia by Jintana enrolled 160 patients at acute infection who were given 3 or 5 cART. The RV217 cohort is still ongoing and has included 93 patients not only in Asia but also in Africa.
Mario Stevenson showed new data on cellular antiviral mechanisms. He isolated RN18, a molecule able to stabilize APOBEC3G from Vif. This product has no off-target effect. We have to congratulate Mario for this work and for being the father of Victoria who his just 2 months old!
Dan Barouch emphasized the fact that pre-ART viremia is correlated to the size of the reservoir. He presented data on neutralizing antibodies and a trial using PGT121 to start in humans within 3 years.
Richard Koup was also on the line of using neutralizing antibodies. He also showed that CCR7 low CXCR5 high follicular CD8 T cells are abondant in germinal centers.
Franck Maldarelli presented data confirming the fact that plasma contains clonal HIV sequences.
Alain lafeuillade discussed the different approaches toward an HIV cure. He showed the failures already obtained, in particular by using HDAC inhibitors. He proposed that unless trying to activate the latent rervoirs, we could try to make them formant for ever. This functional cure would correspond to an integrated, silent HIV, without cART. This can be obtained by initiating cART at acute infection, but we do not know the percentage of patients that would be post-treatment controllers. He presented data from his clinic on a case who is post-treatment controller for 14 years. Functional cure could also be obtained by using antiretroviral drugs able to decrease the viral fitness. Lamivudine is able to do that, as well as Dolutegravir (if the 263 mutation is selected in the integrase, viral fitness decreases of 80%). According to Lafeuillade, these 2 drugs could be used in combo to get a crippled HIV. He announced the launch of a pilot trial within the end of this year to verify this hypothesis. Lamivudine and Dolutegravir will be administered for 6 months in 30 naive patients, then stopped. The trial will include acute patients and early patients with more than 500 CD4 and 4 log viral load (if 3TC can decrease viral load by 0.5 log and Dolutegravir by 2.5 log, this will allow to get low level persistent viremia in order to select the 2 mutations). John Mellors made the point that at stopping therapy the wild type virus might take over. Lafeuillade answered that this will probably be the case but they will compare baseline viral load to viral load 6 months after stopping therapy. They also will use ultra-deep sequencing in order to quantify regularly the 2 mutants. John Mellors and Mark Wainberg have already made a bet on this strategy at the last HIV Persistence Workshop in Miami in December 2013….this bet concerned a very expansive bottle of whisky!
The panel discussion was conducted by Robert Gallo. He started by asking the panel what approach should be preferred: 'reactivating' or 'smoothing and snoozing' latent HIV? No consensus was made but participants agreed that HIV cure research has to be continued in each possible way. The attended focused on the price of this research and the fact that most patients in the world will not be able to afford an HIV cure. It looked like HDAC inhibitors alone have to be abandoned because they are ineffective and gene therapy too because it will be too expansive. HIV cure research must be pursued even if long-acting antiretroviral drugs will soon come to trials. These drugs will be able to keep HIV replication at bay with only 1 intra muscular injection every 6 month….
NB: Both speakers and organizers have been asked permission before publishing this article.
Key words: HIV cure, HIV cure meeting, HIV eradication, HIV reservoirs, NIH, Robert Gallo