HIV-1 stealth mode unveiled

How far are we from an HIV vaccine? Achieving this milestone might be closer than hoped for.

HIV, the causative agent of AIDS, produces a chronic infection by integrating its viral DNA into the genome of the host cell. In this way HIV can exist in a so-called “latent stage”, where it does not replicate, but can rebound at any time under conditions not yet understood. In this “latent” state, the viral genomes are “hidden” from being sensed by host defense systems and can neither be reached by antiviral drugs nor detected in diagnostic tests. Since current anti-HIV therapy cannot cure AIDS, an effective vaccine against HIV is highly desirable.

There are two major types of HIV: HIV-1, the main cause of AIDS, and HIV-2. HIV-2 is less pathogenic to humans most probably because it can be detected by specialized cells of the immune system (i.e. dendritic cells) which become activated and thereafter induce a protective immune response in the host. Interestingly, patients infected with both viruses develop a milder disease than those infected with HIV-1 alone, suggesting that HIV-2 can provide cross-protection against HIV-1.

How can HIV-1 evade the immune system and how do dendritic cells sense HIV-2? HIV DNA is covered by a protein shell, the viral capsid. The capsid of HIV-1 is thought to play a role in immune evasion by protecting the viral DNA from being detected by certain proteins in the cell called DNA sensors. These DNA sensors can recognize non-self DNA and activate an antiviral response. When the capsid of HIV-1 was modified to resemble that of HIV-2, it no longer protected the viral DNA. As a consequence of these modifications, HIV-1 DNA became exposed and could be detected by the DNA sensor cGAS. This recognition lead to the induction of an efficient immune response.

These discoveries offer new possibilities for the development of effective treatments against HIV-1. A successful vaccine could be based on an HIV-1 virus with modifications in the capsid that allow a better detection by the immune system.

HIV-2 (left) infects a dendritic cell (right). The capsid shell (cone) contains the viral genetic material (line) which can integrate in the genome of the infected cell. The DNA of HIV-2 and capsid-modified HIV-1 is sensed by the sensor protein cGAS (radar) which eventually leads to the activation of an efficient immune response. HIV-1 capsid prevents sensing of the viral DNA by cGAS which allows integration of the viral genome into that of the host cell. Image courtesy of dr. Nicolas Manel.

HIV-2 (left) infects a dendritic cell (right). The capsid shell (cone) contains the viral genetic material (line) which can integrate in the genome of the infected cell. The DNA of HIV-2 and capsid-modified HIV-1 is sensed by the sensor protein cGAS (radar) which eventually leads to the activation of an efficient immune response. HIV-1 capsid prevents sensing of the viral DNA by cGAS which allows integration of the viral genome into that of the host cell. Image courtesy of dr. Nicolas Manel.

Resources:

1. Lahaye, X. et al. The Capsids of HIV-1 and HIV-2 Determine Immune Detection of the Viral cDNA by the Innate Sensor cGAS in Dendritic Cells. Immunity 39, 1132–42 (2013).

2. Cox, A. L. & Siliciano, R. F. Making Sense of HIV Innate Sensing. Immunity 39, 998–1000 (2013).

http://www.elsevier.com/connect/scientists-find-invisibility-cloak-that-shields-hiv-1-from-immune-system

http://www.nature.com/news/hopes-of-hiv-cure-in-boston-patients-dashed-1.14324?WT.mc_id=FBK_NPG_1312_NatureNews

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