Because many interesting works were presented, two sessions for presentations were arranged. In the plenary session 1A, Dr. Michael Malim (Dept. of Infectious Disease, King’s College London, London, United Kingdom) talked about “Innate mechanisms of HIV-1 restriction and their viral countermeasures”. He did an account of all innate mechanisms that reduce viral replication of HIV-1 within the cell. He referred in particular to a greater extension to TRIM5α that senses the formation of the viral capsid by inducing the cascade of type I interferons (IFNs). He explained that the IFN-α promotes an antiviral effect that reduces the viral load (VL) and inhibits infection of macrophages and CD4+ T-lymphocytes. Using genomics, they studied the cascade of IFN-α identifying a group of genes that may have antiviral effect, the MX2 gene for example is one which expression inhibits HIV-1 infection. The inhibitory effect of IFN-α is no longer observed when the expression of this gene is silenced. The MX2 gene is present in the human and mice genomes and belongs to the GTPase family of proteins that are induced by IFN-α. This gene has a 63 % homology with the MX1 gene and they dimers that interfere with viral replication, as well as inhibits the entry and integration of the viral cDNA. MX2 also inhibits other primate lentiviruses. At the end, some participants asked him some questions and one of them referred to the possible function of the gene MX2. Dr. Malim replied that the function of this gene is not well known. But, the important thing was that if you inhibit the cascade of IFN-α in the simian immunodeficiency virus (SIV) model, there is an increase in the VL. He also answered to another question that the MX2 gene is only expressed at high levels in the presence of IFN-α.

The session also included the lecture “From HIV inhibition to HIV escape: CCR5 conformations are differentially exploited by chemokines and R5 HIV-1” by Dr. Bernard Lagane (Institut Pasteur, Paris). He began exposing the paradoxical observation of low inhibition of viral infectivity in the presence of chemokines with high affinity for the CCR5 receptor. Then, he hypothesized that CCR5 has different conformations to which the chemokines and the virus bind differentially. He explained that CCR5 has different conformations that interact differently with a number of chemokines. On the basis of his results, there are conformations of CCR5 that show more affinity for gp120 than to chemokines. This might explain the limited inhibitory capacity of the chemokines. Chemokines that recognize a given conformation with the higher affinity will show a greater inhibitory effect. In his model, CCR5 only has two conformations: one when it is coupled to an intracellular G-protein and another when it is free. At the end of the conference someone asked him whether he think that the two conformations of CCR5 must be in dynamic equilibrium or not. He agreed and speculated that such equilibrium might depend on the activation state of the cell and there must be usually a higher percent of free CCR5 and that conformation enables the viral entry.

In the session 1B, Dr. Carine Van Lint (Université Libre de Bruxelles, Brussels, Belgium) delivered a talk on “Molecular mechanisms of HIV-1 post-integration latency”. She showed some results identifying a group of human proteins forming a complex that interacts with the chromatin and promotes viral latency. In this regard, she proposed to develop therapeutic inhibitors targeting these proteins to stimulate the viral replication in reservoirs. In another presentation, Dr. Nevan J. Krogan (University of California, San Francisco, United States) in his lecture "Using systems approaches to study HIV biology" explained that they are carrying out experiments in Jurkat cells transformed to express some HIV-1 proteins. Then, the interactions of these viral proteins with the human proteins are studied. Later, they plan to purify up to hundreds of human proteins to identify and study in detail such interactions. As an example, he showed the case of Tat protein. Tat interacts with two of those isolated human proteins and he proposed to seek drugs to inhibit that interactions. Also, he explained that Vif interacts with three proteins in a complex that will be crystallized soon, to determine its structure, and they hope to develop inhibitors to this complex. In general, he said there are 415 human genes that are under the influence of HIV-1 proteins. They have sequenced such genes in a number of people living with HIV/AIDS and in people who show true viral control, trying to find any genomic imprint that would show some correlation with greater susceptibility or resistance to the virus. They are also studying the disturbances in cellular mechanisms of post-transcriptional modifications caused by HIV-1 infection. There are evidences that accessory proteins of the virus affect the function of the proteasome. For example, they are studying the hyper-ubiquitinacion of human proteins caused by Vif.

This session was also split due to the high number of presentations. In the session 2A, Dr. Persephone Borrow (Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom) in her lecture “Innate immune responses in acute HIV-1 infection: protective or pathogenic?” explained that natural killer (NK) cells are very important to control viral replication early after infection. Because the innate response is efficient on controlling viral replication, escape mutants resistant to type I IFNs (IFN-α) are selected and she showed viral sequences from different patients. She was asked whether the IFN-β is also important or not. She said that it is also important.

Later on, Dr. Eric Hunter (Emory Vaccine Center, Atlanta, USA) delivered his lecture “The replicative capacity of transmitted HIV-1 contributes significantly to CD4 decline independent of VL and host contributions”. He showed results obtained in discordant couples, where the viruses with low replicative capacity that maintain a viral load less than 1000 copies of viral RNA never cause a drop in CD4+ T-cells counts below 350 cells/microliter. He speculated that this might be generalized to any viral isolate independently of the subtype. He also explained that if there is viral transmission in a couple that shares its HLA haplotype, then the virus will show greater adaptability and the progression to AIDS would occur sooner. Additionally, they found significant correlations between the viral replicative capacity and the sequences of the gag gene in the viral isolates. A viral isolate with a high replicative capacity would promote greater inflammation, depletion of CD4+ T cells and greater microbial translocation from the gastrointestinal system to the systemic compartment. Because of that, he thinks that a vaccine that promotes a cellular immune response against isolates of high replicative capacity might be effective to prevent the progression to AIDS. Someone in the public asked him on which virus subtypes were investigated, and he answered that only subtype C isolates, because the study was done in Gambia. This observation emphasizes the importance of conducting similar studies in cohorts of patients infected with non-C subtypes of HIV-1, prior to generalizations. Dr. Leonid Margolis (NIH, Bethesda, United States) in his lecture “HIV exploits seminal cytokine network to promote its transmission to cervico-vaginal tissue. Ex vivo study” explained that the presence of IL-7 in the seminal fluid promotes greater efficiency of viral transmission in sexual relationships by inducing the activation of T lymphocytes. Although the results were obtained in ex vivo experiments he hypothesized that the presence of low levels of IL-7 in seminal fluid could explain the low transmission level in some couples. Someone in the public asked Dr. Margolis whether he had knocked-out the IL-7 gene expression to observe the consequences and he said that it would be done in the future.

In the session 2B, Dr. Victor Appay (Hôpital PitiéSalpétrière, Paris, France) talked about “Deconvoluting the molecular arm race between HIV and the CD8+ T-cell response: Lessons from studying the HLA-B27 Gag specific response”. He showed how the immune response by cytotoxic T lymphocytes (CTLs) controls the viral load when new viral variants are selected. These viral isolates known as mutant escapes have mutations that generate epitopes with lower avidity to the T cell receptor (TCR). This fact is explained because T cell clones with high avidity TCRs tend to be polyfunctional and allow a better viral control. Finally, in this competition the virus wins because the capacity of the immune system to generate compensatory mutations to generate an optimal TCR is limited. Therefore, an optimal CD8+ T lymphocytes response would be the one recognizing important determinants of the virus with high sensitivity (avidity) and, in turn, showing some crossreactivity versus different epitope variants. He concluded that, for vaccination purposes, immunogens that induce high crossreactivity for several viral proteins formulated with adjuvants that promote T cell clones with high avidity TCR sequences (with the lowest barrier of activation) should be preferred.

Session 3. Inflammation, immune activation & pathogenesis

The session began with the lecture of Dr. Daniel Douek (Vaccine Research Center, NIH/NIAID, Bethesda, United States) entitled “The good, the bad and the ugly of immune activation”. He versed on the hypothesis that blocking the function of type I IFNs would result in an improvement of the chronic infection with SIV because this lowers the immune activation. To prove it, he obtained an anti-human-IFN-α antagonist that he tested in Cynomolgus monkeys. He observed that in acute phase, the viral load and inflammation increased similar to the placebo group. However, in chronic phase, the viral load fell with the inmunoactivation. In terms of survival to the viral challenge, it was noted that monkeys treated in the acute phase died a year after because they progressed to AIDS quickly. Then, the hypothesis was re-written as IFN-α promotes a better response early in the infection and a bad response in the chronic phase. They assessed the hypothesis for the acute phase using an in vivo model of a high dose intrarectal challenge. They observed that monkeys injected with IFN-α were more difficult to infect and when they did, the viral isolates showed less variability. The protection was associated with the presence of NK CD56+ cells and a lower CD4+/CD8+ T cell ratio due to an increase in the effector memory CD8+ T population with a decrease in the amount of central memory CD4+ T cells. He also replied that they did not know on the possibility that some IFN-γ secreted during the acute phase of infection would be influencing the results, when questioned.

Session 4. Clinical & translational research

It was started by Dr. Marina Cavazzana-Calvo (Université Paris Descartes, Paris, France) talked about “Gene Therapy approach for HIV-1 infection”. She discussed on the case of the Berlin patient and how his group think to carry out a similar approach in other patients. The patient’s stem cells would be obtained and transduced in vitro with viral vectors and then reinfused again to the same irradiated patients. She showed some results in a SCID mouse model where an 85 % survival rate of the infused cells was achieved. However, she also discussed some limitations of the strategy. In the first place, she said that when onco- and retroviruses are used, there is always a minimal risk (but real) to generate a tumor. In addition, he said that the infectivity of the vectors is low, in the range of 0.001-0.38 %, taking into account all the research done in the USA. To the question, would the human gene therapy be limiting to implement? She replied that the main problem would be ethical. You must obliterate the whole immune system of the patient prior to restocking with the transfected cells. This implies that you must be sure enough that the procedure is going to work and it would bring something positive to the patient. Otherwise, there is a huge risk for the patient’s life. Next, Dr. Dan Barouch (Beth Israel Deaconess Medical Center, Boston, United States) presented results on the use of Adenovirus (Ad) as vaccine vectors. He explained that the Phase IIb study HVTN 505 which consisted of stimulation with naked DNA and re-stimulation with Ad gave a result similar to that of the STEP trial, being a failure. Thinking in future studies, he showed a comparison among Ad serotypes 5, 26, 35 and 48. He showed that they have different tropisms, different cellular receptors, differential gene expression, etc. For instance, Ad5 causes an increased inflammatory response than the Ad26 promoting greater expression of PD-1 in memory T cells which suggests a lower functionality. It might explain the lower responses of Ad5 in comparison to Ad26 after boosting immunizations, although the primary response is higher. One of the most interesting conferences for their practical implications was delivered by Dr. Jacques Leibowitch (Infectious Disease Department, Raymond Poincaré Hospital, France) entitled “Four days a week and less on proper antiviral combinations provided long-term maintenance on 84 Patients’ HIV / The ICCARRE PROJECT”. He showed results in 84 patients who underwent a period of 3 years under antiretroviral treatment, with a regime of four generic drugs that combined a non-nucleoside reverse-transcriptase inhibitor (NNRTI) with three nucleoside reverse transcriptase inhibitors (NRTIs) during four and just one day a week. It seems that in these conditions the viral load remained undetectable and the CD4+ T cell counts remained unaffected.

Session 5. Strategies for HIV control & cure

Dr. Steve Deeks (UCSF, San Francisco, United States) explained “Why curing HIV might be easier than assumed”. He observed, in relation to the cure of the Mississippi patient, that it suggests that patients receiving antiretroviral therapy within the first two weeks of infection would avoid the formation of viral reservoirs (primarily in central memory T cells). He also said that there is a patient of Dr. Fauci who eradicated the virus after 12 years under suppressive therapy. Although it does not seem to be something common, perhaps among patients who have been in therapy for a long period of time there might be some of them who have eliminated the virus. On the outcome of the French cohort Visconti, his opinion was that it cannot be generalized. Then he spoke about the drug Vorinostat that activates viral reservoirs and the antibiotic rapamycin that also decreased the reservoirs in some HIV+ patients who received kidney transplants. The latter antibiotic generally decreases the inflammation, as well as the activation status and proliferation of T-cells. He thinks that the reduction of inflammation could in turn reduce the viral reservoir. He said that they are ready to publish results in patients under antiretroviral therapy that were reinfused with allogeneic stem cells and were apparently cured from the infection. Dr. Asier Saez-Cirion (Unité des Régulations des Infections Rétrovirales, Institut Pasteur, Paris, France) in his talk “Natural and treatment induced control of HIV/SIV infections” evidenced that some elite controllers will need antiretroviral treatment in the future, given the increases in viral replication observed. He also commented on the case of a monkey infected with SIV which was depleted of CD8+ T cells and the VL remained undetectable. It shows that some mechanisms independently of CD8+ T cells may also control the viral replication efficiently. Perhaps, something similar happened with the virological post-ART controllers of the Visconti cohort, because they did not have protector HLA alleles. Someone in the audience asked Dr. Saez-Cirion about the replicative capacity of the isolates of the virological post-ART controllers taking into account the sequence of the gag gene, and he said that the study was in progress, but they cultured the virus and high viral titers were observed. Then, they concluded that these viral isolates have good replicative capacity.

This was the last session of the meeting. Dr. Punnee Pitisuttithum (Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand) started it commenting on the results obtained in phase III RV 144 clinical trial. He explained that the greatest correlate of protection found was the antibody-dependent cell cytotoxicity (ADCC) in the sera. It also correlated with high titers of IgG and low titers of monomeric IgA. In other words, they found statistically higher IgA/IgG ratios in volunteers who became infected in comparison to the non-infected match pairs.