oncolytic properties 29.
The AIDS-‐causing HIV-‐1 belongs to the genius of lentiviruses and is characterized by a conical shape of the core of the mature virion. Members of this group carry this name because of the long asymptomatic phase preceeding the first symptoms 12. HIV-‐1 expresses six accessory proteins that will be discussed below. These gene products control transcription, gene expression and assembly and counteract restriction factors encoded by the host 12. The primer used by lentiviruses is the tRNALys3.
In latin Spuma means foam. The members of the Spumaviruses produce vacuolization of cells, hence resulting in a foamy-‐like histological aspect. The human foamy virus is a well-‐studied member of this group. The pol gene products arise from a splice transcript. Unlike other retroviruses, this genius of viruses is characterized by virions that carry high amounts of reverse-‐
transcribed DNA. Accessory proteins shared by the members of this group include a transcriptional transactivator. The primer used is generally tRNALys 12.
1.1.6 The Acquired Immunodeficiency Syndrome (AIDS)
The AIDS is a severe disease affecting more than 35 millions of people around the world, as published by the UNAIDS report on the global AIDS epidemics 2013
30.
In the early 1980s, young men with typical immunodeficiency symptoms were hospitalized in Los Angeles, New York and California 31,32.
As mentioned previously, biochemical and genetic tools for studying retroviruses existed in that decade and they were used by Researchers at the Institut Pasteur and in the United States to characterize the virus extracted from CD4+ T cells coming from AIDS patients. Barré-‐Sinoussi and colleagues isolated and described a virus that was able experimentally to infect T lymphocytes
extracted from cord blood 22 and called it Lymphoadenopathy Associated Virus (LAV).
The team of Robert Gallo, had suspected that the causing agent of AIDS was of retroviral origin and possessed T-‐cell tropism but at that time attributed it to the human tumor retrovirus HTLV-‐I 33. The virus was later called HTLV-‐III by the same team.
In 1986, the virus was finally named the Human Immunodeficiency Virus (HIV), in reference to the disease it produced 34.
Transmission of HIV-‐1 from one person to another happens during sexual intercourse, injecting with contaminated needles, or by blood transfusion 35. Mother to child transmission during delivery or after breast-‐feeding is another important route of spreading 35.
The first events of HIV-‐1 infection seem to implicate a local spreading within cells residing in the mucosa and in the epithelium, such as dendritic cells (DCs), CD4+ T cells and macrophages 36-‐38. Primary infected cells subsequently migrate to the lymphoid organs and seed the virus by direct cell-‐to-‐cell contact or by the release of newly produced cell-‐free viruses, which enter new cells 39.
When HIV-‐1 gp120/gp41 glycoproteins interact with the lectin receptor DC-‐
SIGN at the surface of DCs, the virus can be either endocytosed and degraded within lysosomes or by targeting to the proteasome 40,41. Another route for entry into DCs is mediated by a host-‐derived glycosphingolipid present in the virion envelope that binds to an unknown receptor, with SIGLEC-‐1 being a potential candidate 42. This interaction allows the virus to escape degradation and join immunological synapses, from where new target CD4+ T cells can be reached
12,43,44.
During the acute phase of infection, a large fraction of CD4+ T cells are infected and high amounts of virions are synthesized and released from cells 39. As CD8+
T cells fight against the pathogen and high doses of type I interferon (IFN) and cytokines are released, infected individuals commonly experience flu-‐like
symptoms 45-‐47. The immune response mediated by cytotoxic T cells and B cells producing antibodies permits to moderately recover the level CD4+ T cells for a few weeks 47. At that point, HIV-‐1 already integrated into the host chromosomes and latent reservoirs starts to be established, and infected individuals can have a total absence of HIV-‐1-‐related symptoms for nearly ten years 47. Unfortunately, in the meantime, the virus continues to replicate and spread via the various lymphoid organs.
At the terminal stage, the disease causes a high destruction of the CD4+ T cells, which decrease below 200 cells per mm3 of blood, leading to immune suppression and the subsequent unavoidable infection by opportunistic pathogens as Candida albicans and Pneumocystis jirovesii 48.
The AIDS pandemic is likely to have originated in central Africa as a result of cross-‐species transmission of a chimpanzee lentivirus to humans. Studies of sequence homology between SIVcpz and HIV-‐1 have shown that the human lentivirus is derived from the simian one 49. The second type of HIV, named HIV-‐
2, is less pathogenic and transmissible and thus less frequently leads to AIDS.
Although the two viruses have a similar genome organization, they are derived from different SIV strains 49. Whereas HIV-‐1 comes from the SIVcpz, HIV-‐2 arose from a zoonosis with the sootey mangabey monkey, Cercocebus atys. Instead of the Vpu accessory protein, HIV-‐2 possesses Vpx, which counteracts a block to reverse transcription within DCs and macrophages 50. Additionally, HIV-‐1 and HIV-‐2 highly diverge from their env sequence. In fact, it was observed that there is already 25% of divergence of the gag, pol and env sequences within the strains of each type, as reviewed by Reeves and Doms 51.
A combination of nucleoside or non-‐nucleoside reverse-‐transciptases inhibitors and protease inhibitors constitute an aggressive therapy for maintaining the virus load at a low level 52,53. The highly active antiretroviral therapy (HAART) allowed the life expectancy of individuals to reach nearly normal life spans 54. Thanks to these combined anti-‐retroviral therapies and efforts employed in prevention education, new infections have diminished of near 30% compared to
2001 (UNAIDS report, 2013). However, the pathogen is still far from being eradicated as HIV-‐1 has rarely been totally cleared from an individual 55,56 and a vaccine is still missing.
The reasons why the search for an effective vaccine has been unsuccessful until now could be in part the inability of the immune system to detect a dormant virus and inherent to the tropism of the virus that targets to destruction the immune cells themselves 44. Another important point that could explain the failure of the immune system to detect HIV-‐1 and mount a robust response is that this virus does not productively infect the DCs that are antigen-‐presenting cells (APCs), that prime the immune effectors to kill infected cells. Yet the antigen from these cells is being presented. It seems likely that the APC needs to be activated for the priming of effector T cells to be efficient, an unproductive infection leading to no immune activation will fail to fulfill this prerequisite 44.
The innate immunity actors and consequences of their activation will be introduced further below.
1.1.7 The structures of the HIV-‐1 virion and genome
The HIV-‐1 gag orf codes for a precursor polyprotein of 55 kDa in size, called Pr55gag, which is cleaved within the virion into the MA, the CA, the NC proteins and p6 that is involved in viral budding 57.
HIV-‐1 membrane form a spherical particle that has a diameter of approximately 110 nanometers (figure 4). The virion contains a conical-‐shaped CA protein complex that is composed of 216 hexamers and 12 pentamers, linked between them by the C-‐terminal domains of CA 58,59(figure 4).
The viral particle core is enclosed by a layer of MA proteins, in turn surrounded by a lipid bilayer coming from previous infection events.
The MA protein form hexameric higher-‐order complexes, which encapsulate the viral core. These complexes interact with different virion components and seem