Last but not least, how to stop the epidemic and achieve a cure? Comprehensive reviews were provided by Virginie Supervie and Francois Dabis as well as Myron Cohen. We need to track the current state of the epidemic, early diagnosis of the HIV infection, prevent the acquisition and the transmission of HIV. Our preventative tools have grown in the past few years with the acknowledgment of the impact of ART as a tool for prevention. Myron Cohen discussed the different prevention strategies and interventions in the uninfected and infected individuals. Factors associated with amplified transmission include those associated with infectiousness such as blood and genital tract viral load, sexually transmitted diseases (STDs), viral clade and acute infection and susceptibility for the acquisition of the virus such as STDs among others. Joep Lange reiterated the strong arguments in favor of early therapy and its individual and public health benefits in the implementation of TasP. Francois Dabis’ recommendations for ending the epidemic within the next 20 years were to go to the communities, counsel and test, treat everybody, promote condom use and male circumcision and harm reduction.
Is there a possibility of a cure for HIV? In his update on reservoirs Lian Shan showed the complexity of HIV-1 integration, in particular in memory precursor CD4+ T cells and the potential role of CTLs boosting in the elimination of infected cells. The pharmacological approaches by Ole Schmeltz Sogaard covered multiple immmunologcial interventions including neutralising antibodies beside therapeutic HIV vaccines, Anti-PD-L1 Ab, NK cells, peg INF-alpha and TLR agonists and others. Gene therapy and bone marrow transplantation were discussed by Joachim Hauber and Jan van Lutzen. Gene therapy has had limitations because of the low number of transduced cells and genotoxicity. Zinc finger nucleases (ZFN) technology has the disadvantages of the possibility of off-target effect and chromosome instability. Joachim Hauber presented the next generation LTR-specific Tre-recombinase which targets a majority of HIV-1 isolates. It attacks the reservoir directly and is presently expanding to other subtypes. Anne Gatignol discussed the new therapeutic target in Gag RNA accessible to ribozyme and RNA interference molecules and in particular hepatitis delta-derived ribozyme to target HIV-1 RNA with long-term inhibitory activity suggesting that this type of molecules might be used in combination gene therapy or as drugs.
The development of an HIV/ AIDS vaccine has been a long and difficult endeavor, which so far was met with many failures. The hopes and challenges in HIV vaccine research were discussed at the 2014 ISHEID Conference. Vaccine challenges include the genetic diversity and mutability of HIV-1 that create a plethora of constantly changing antigens, the structural features of the viral envelope glycoprotein that disguise conserved receptor-binding sites from the immune system, and the presence of carbohydrate moieties that shield potential epitopes from antibodies. Indeed, HIV-1 gp120 contains a number of features that help the virus evade the host’s humoral immunity, including variable loops, N-linked glycosylation, and conformational flexibility that disguise the conserved receptor-binding sites from the humoral immune system. The presence of carbohydrate moieties on gp120 shields potential epitopes from binding to antibodies, as shown by Czernekova et al.. By partially removing N-glycans from gp120 they increased the reactivity of a panel of gp120-specific broadly neutralizing antibodies and sera from HIV-1-infected persons.
The successful development of an HIV vaccine is one of the ten big challenges highlighted by Marc Wainberg. He also pointed out that there is a very limited rate of success in the development of vaccines to all forms of sexually transmitted disease, with the obvious exception being Human Papilloma Virus. As reviewed by Marc Girard, the first efficacy trials for an HIV vaccine attempting to elicit protective antibodies against the viral envelope, VAX004 and VAX003, did not prevent HIV-1 infection or impact the level of viraemia in those infected. The next set of antigens used in clinical efficacy studies were designed to test whether T cells could protect against HIV-1 infection. Neither the STEP trial (Ad5 gag/pol/nef) nor HVTN 505 trial (DNA/rAd5 gag/pol/nef/env prime/boost regimen) could protect against HIV-1 infection, or reduce early plasma HIV-1 levels. The proof of concept that it is possible for a vaccine to elicit protective immunity that blocks infection came from the RV144 clinical trial in Thailand that yielded a 31% reduction in HIV-1 acquisition using a canarypox-gp120 prime-boost vaccination regimen. Moreover, as highlighted by Marc Girard, new surrogate markers of protection came from the RV144 trial, including the presence of V1-V2 targeted IgG. The V2 loop contains the binding site to the α4β7 receptor of CD4+ T cells involved in T cell migration to the GALT, and it is also part of several neutralization epitopes, including those recognized by broad neutralizing antibody (bNAb) VRC26.08 at the apex of the HIV-1 spike. The RV144 trial also showed strong correlation between protection and IgG that target the C1 domain of gp120 and promote ADCC. Several studies that addressed the question of correlates of protection from infection or from the disease were reported at the ISHEID Conference. The resistance to HIV-1 infection among exposed seronegative partners in HIV-discordant couples was associated with higher frequency of CD8+ T cells expressing CD107a/b and IFN- ascompared to unexposed subject, suggesting a protective role of HIV-specific CTLs. The protective role of CTLs was also suggested by the finding that HIV controllers exhibit high frequency of CD8+ T-cells displaying the phenotype CD38negHLA-DR+ and exerting ex-vivo cytotoxic activity, the frequency of these cells being correlated with the capacity of CD8+ T cells to inhibit viral replication. A novel experimental approach was presented to analyze lymphocytes from post treatment controllers (PTC), in particular the presence of replication competent HIV, following transplantation of Rag2-/-c-/- (Rag-hu) mice with CD4+T cells from the PTC and subsequent engraftment with human T cells.
Broadly reactive neutralizing antibodies (bNAbs) have been found in select individuals living with HIV, demonstrating that humans are capable of making broadly neutralizing antibodies. They show potent cross-clade neutralizing activity against 70-90% of HIV-1 strains. They are remarkably protective against i.v. or mucosal HIV or SHIV infections in animal models, and they can suppress active infections in mice and macaques. bNAbs develop over a period of a few years (2.5 years average) in only 15-20% of HIV-1 infected persons, and they are the result of a long affinity maturation of B cells and extensive mutation of the B cell lineage that seem to be driven by long antigenic exposure. A vaccine should offer protection against the majority of HIV strains. Hence, a number of questions should be addressed: i) are we able to design a vaccine that induces rapid production of V1V2-specific protective Abs? ii) how to transfer the knowledge of cross-specific antigens into immunogens that will induce powerful protective response following vaccination? iii) do we know enough about B cell maturation and plasmocyte differentiation? iv) which immunogen to develop considering that broadly neutralizing Abs that were identified are hypermutated ? it may be needed to stimulate a succession of antibodies that recognize epitopes and neutralize them in a series of vaccination; v) how to induce the correct B cells and stimulate them to produce Abs with a high degree of affinity maturation ? vi) how to induce humoral memory that is mediated by long-lived antibody-secreting cells? vii) successful vaccines (smallpox, hepatitis A, YF) elicit broad integrated responses involving all effectors, including innate (TLRs), NK, Th1/Th2 responses. Considering that innate immunity influences both the qualitative and quantitative features of adaptive immunity, we should identify the innate correlates of protection.
The question still arises whether a vaccine that does not prevent infection but reduces HIV levels and preserves uninfected memory CD4+ T cells would benefit the recipient. Several studies were presented at ISHEID conference reporting the development of new therapeutic vaccine candidates and their safety in preclinical and clinical trials. A new technology was reported, conferring one-step in vivo production in targeted cells of an efficient and safe DNA-virus-like particle (VLP) expressing gagV3(BCE), and leading to the presentation of immunodominant HIV antigens. In preclinical studies, GenePro, a lentiviral therapeutic vaccine that includes 7 out of 9 HIV genes, was able to induce in a single high dose a long-lasting and polyfunctional T-cell response in the nonhuman primate model. Another lentiviral-based therapeutic vaccine was presented, generating a strong, specific and long-lasting T-cell response in mice, and currently evaluated in HAART-treated patients in a phase I/II vaccine trial. A different approach consisted in the induction of neutralizing antibodies to HIV-1 matrix protein p17 that, through the interaction of its NH2-residing epitope AT20 with specific receptors, acts extracellularly as a viral toxin. A peptide-based immunogen, AT20-KLH, was used in a phase I trial and shown to generate p17-specific antibodies able to neutralize its binding to cell receptors in HAART-treated patients, and still detected two years after the first injection.
Finally, a novel approach to protect with antibodies against an infectious disease was recently developed: the vector-immunoprophylaxis (VIP) or Vector-mediated Ab gene transfer, which aims at eliciting passive immunization using an AAV vector that expresses the H and L chains of a monoclonal bNAb (such as VRC-01, VRC-07…). This ‘gene-therapy’ approach has been successfully tested in animal models (BLT mice) conferring a full protection against mucosal HIV transmission, suggesting that a sufficiently high circulating concentration of bNAb might substantially reduce the probability of sexual transmission of HIV between humans.
The search for a HIV vaccine is a long story, starting in the early 90s by the first clinical trial performed in humans by Daniel Zagury and a long road is still ahead. Promizing strategies are, however, in the pipeline.