New Concepts in HIV Immunopathogenesis, Treatment and Vaccines
Summary of an IAS 2011 affiliated event. Rome, July 16th 2011 - 8:30 - 18:00
This day-long meeting was hosted by the Sapienza University of Rome and co-organized by the American Office of AIDS Research and the French Agency for AIDS Research (ANRS)
The event was introduced by Brigitte Autran who explained the basis of the meeting. She said that both treatments and vaccine research are not currently satisfactory and that the "familly" of researchers has to meet in such kind of event to define new ways of controlling HIV.
Gary Nabel, Director of the Vaccine Research Center, NIAID, gave the opening keynote, talking mainly about parameters of viral control. Can broadly neutralizing antibodies confer protection against HIV? Non-human primate models of HIV acquisition show that some vaccines can reduce by 50% the risk of virus infection. This effect might be mediated by neutralizing antibodies. HIV infection is first a disease of mucosal lymphoid tissue. Consequently, some vaccine candidates are currently primed in animals directly in the ileum: this induced high levels of Ig A response. After viral rectal challenge, the protection was indeed highly increased. Advances are being done to design such antibodies in humans, that could be used therapeutically to control viremia or reduce the HIV reservoir.
The first session was focused on NEW CONCEPTS IN IMMUNOPATHOGENESIS AND VIRUS CONTROL.
Ashley Hase presented a vaccine concept based on timing and location. The monkey models show that there is a hudge opportunity to act during the "eclipse" phase at acute infection. There is at this stage a local expansion in the cervix of the small founder population with an influx of target cells. Several signaling systems are involved in this local expansion. SIV-delta nef live attenuated vaccine provides the best protection in animal models. The challenge phase with SIV mac 251 is done vaginally. This protection could be due to the rapid intervention of CTLs on the small founder viral population. Tissue antibodies against Env were also found that are probably produced locally. Submucosal plasma cells are supposed to produce these antibodies. The speaker pointed out that mecanisms of protection could be different in the rectal mucosa.
Amalio Telenti gave the genomic view of host and virus interactions. When cells get infected there is rapid downregulation of many cell genes. But lately there are 499 particular genes that are upregulated. Genomics also help to determine if , concerning innate imunity, there is restriction factors sharing the signature of genes of TRIM5a and APOBEC3G. A map de 57 genes is established which are identified under positive selection, inluding IFI44, HMGA1, SP110, FAS. Finally it also helps to identify correlates of progression betwen macaques and humans, looking at human rapid progressors, or -on the contrary- non progessors, and Rhesus macaques and shooty mangabeys. For example, CASP 1, CD38, LAG3, TNFSF13B were shown to be involved in rapid progressors.
The second session focused on NEW CONCEPTS IN MOLECULAR MECHANISMS OF VIRAL CONTROL.
Douglas Richman gave an overview on the difficulties to achieve control of the HIV reservoir. He first recalled that there are 2 opposed theories: smoldering viral replication on ART, and virus production by long-lived cells. He recaped the arguments against ongoing replication: no resistance, no genetic evolution, no impact of HAART intensification. The cellular reservoirs reside in CD4+ T cells, may be macrophages, hematopoietic stem cells and multipotent stem cells, and may be in other unknown cells. Anatomic reservoirs reside in the brain, and probably the genital tract. All lymphocytes in all anatomic sites are not the same, as showed by Joe Wong group. Different mechanisms have been described to be involved in the maintenance of the reservoir. But our understanding of mechanisms of latency is incredibly primitive, according to the sepaker. Assays to measure the reservoir have barely been validated and we still need new, more precise assays. The dynamic range of current assays only measure the tip of the iceberg. Finally, another challenge to achieving a cure resides in ethics: safety of drugs means a lot when patients are well on ART regimens.
Marcus Altfeld then spoke on the role of NK cells in controlling HIV. These cells are a polyclonal population. They recognize HIV-infected cells and their KIR receptor genotype is correlated with control of viremia. NK cells are expanded at acute infection. KIR3DS1+ NK cells have anti-HIV activity. This activity is demonstrated in vitro, and confirmed in vivo. Can we exploit this activity for vaccine design? Future will tell...
Monsef Benkirane then presented his recent data about SAMHD1 as the specific HIV restricting factor in dendritic cells and myeloid cells, counteracted by Vpx. Would decreased levels of SAMHD1 levels allow for better immune control of HIV infection? The study of SAMHD1 involvement in non human primates and elite controllers will allow answering the question.
The third session focused on NEW CONCEPTS IN ERADICATION OF VIRUS RESERVOIRS.
Christine Katlama stated that the best should be to treat every patient with ART, but that this is not possible in the real world. Consequently it is mandatory to find -at least- a "functional" cure. There are patients who have been treated at acute infection and when ART was stopped, they still continued to suppress viral replication and showed a low reservoir (proviral DNA at 83 copies/million cells). On the contrary, patients who are totally controlled by ART viremia <1 copy/ml, still experience inflammation. She hypothesized that the antiretroviral choice could have a role and showed data where patients on Nevirapine reached more frequently than those on Efavirenz HIV RNA < 1 copy/ml and lower levels of inflammation. She finally reviewed the new strategies proposed to target the reservoir, from ART intensification to IL-7 treatment, through the anti-PD1 approach. She proposed a strategy combining ART intensification, anti-inflammatory agents and specific drugs against latent infection.
Rafick Sekaly began his talk saying that in terms of HIV eradication all is about synergy between scientists. He first made a difference between latency and persistence. In the first situation, the is no or little replication. In the second one, replication can occur. He then moved to the mechanisms of HIV persistence in cells. Central memory cells have the capacity to persist. IL-7 is necessary for homeostatic renewal and IL-15 prompts cell maturation and viral production. Latency may also be sustained by negative regulators like PD-1 or by chemokines. There is a strong correlation between cells highly espressing PD-1 and the reservoir. In macaques, anti PD-1 rescues viral replication and immune functions. Consequently, eliminating TCM cells could be an important part of an eradication strategy. With this PD-1 marker, the goal would be not to remove all TCM cells but only those bearing proviral HIV DNA.
Steve Deeks focused his talk on the role of T cell activation and inflammation. There is no correlation between T cell activation and residual plasma viremia in blood. But in the gut, T cell activation correlates with persistent HIV RNA. Going back on the data just presented by Sekaly, Deeks mentioned that a clinical trial using a monoclonal antibody against PD-1 is planned.
Javier Picado reviewed published studies of ART intensification. All of them showed no effect on residual plasma viremia. Only the Buzon study showed some change in the level of 2 LTR circles, and the Yukl study on unspliced RNA in the ileum.
Jan van Lunzen spoke about gene therapy. He reviewed what are currently the identified antiviral genes, some of them working before, others after, viral integration. In his view, if all trials of gene therapy have currently failed, it is because we were unable to transfer sufficient numbers of modified cells to the host. Targetting stem cells, in his view, would be more adequate than targetting CD4 cells.
Stefano Vella discussed the role of the gut as a reservoir and as a source, or not, of viral rebound. He emphasized the need to sample different parts of the gut in experiments, and to explore drug pharmacokinetics in this compartment. May be it will be necessary to enhance gut targetting with future strategies. Brigitte Autran concluded this session by showing data from Christine Rouzioux group on the control of the TCM reservoir in HLA B27/B57+ patients. She proposed to develop strategies aimed at protecting TCM cells. She challenged the presentation of Doug Richman who do no longer think that ongoing replication is important in the maintenance of the reservoir.
The last session focused on NEW CONCEPTS IN VACCINE STRATEGIES.
Dan Barouch discussed also the correlates of protection in SIVmac251 vaccinated monkeys. The first study used adenovirus/poxvirus and involved 40 monkeys. Protection against heterologous, repetitive intra rectal challenge was partial. In the Ad26/MVA group, a decrease in viral load of 3.56 log was observed. Several analysis were performed to define the parameters of this partial protection. Env ELISA titer, Tier 1 Nab, ADCC were found correlated with acquisition; Gag breath and Gag ELISPOT with virologic control. The second study involved 40 monkeys immunized by a Ad35/Ad26 regimen. After challenge, the GagPol Env vaccine group, compared to GagPol or controls, had the better response.
John Mascola talked again about inducing neutralizing antibodies by vaccines. First, during infection, some patients experience broad neutralizing antibodies. Then the antibodies can be analyzed to define specific epitopes. Using this approach several antibodies have been described during the last few years. 454 deep sequencing of antibody heavy and light chain genes can help in vaccine design.
Yves Levy spoke about ways to target Dendritic Cells. His strategy is to develop monoclonal antibodies and his team has already produced 100 monoclonal antibodies ; one example is anti-CD40Gag/Pol//Nef.
Giuseppe Pantaleo presented the immunogenicity of DNA-C/Poxvirus Vectors/gp120 vaccine regimens in Non Human Primates. He emphasized the interest of using replication competent vectors.
Concluding remarks were given by Françoise Barre-Sinoussi. She pointed out the importance of learning from primate models and human cohorts. Early events in the mucosa are critical for HIV pathogenesis and the establishment of the reservoir. Inflammation has also an impact on HIV persistence and is an important issue to address. Ongoing replication in other compartments than blood has still, in her view, to be addressed. Restriction factors have to be considered for the positive or negative effect of innate immunity. We need new biomarkers and tools to monitor HIV persistence. Novel therapeutic and vaccine strategies are needed and will have to move into clinical trials. She remains optimistic for the future for functional cure, combining different approches. Although her laboratory is mainly involved in pathogenesis and vaccine research, as IAS President elect she wants to bring scientists back to the search of a cure and initiated an alliance for HIV cure. The aim is to define a global scientific strategy defining research priorities for an HIV cure. A first draft will be available soon and broadly distributed to get insights not only from HIV scientists but also scientists outside the HIV field.
Key words: HIV, HIV new concepts, HIV pathogenesis, HIV treatment, HIV vaccines, IAS, IAS HIV Cure