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The spread of HIV: optimal adaptation to the human host

A new study led by the virologist and Leibniz Award winner Frank Kirchhoff from Ulm might be about to provide an explanation as to why only one of several independent transmissions of simian immunodeficiency viruses (SIV) from chimpanzees to humans led to the global AIDS pandemic. The researchers now hope that these new findings will contribute to the search for new strategies to prevent the further spread of AIDS viruses.

Only HIV-1 M is able to effectively adapt to its host

Prof. Dr. Frank Kirchhoff © University Hospital Ulm

Only the HIV-1 M group was able to optimally adapt to its new host after being transmitted from chimpanzees to humans. This might be an important reason why only one of several independent transmissions is responsible for most of the AIDS pandemic. An international team of researchers led by Frank Kirchhoff has shown that the HIV-1 M (major) group alone, which has led to more than 90 per cent of all infections worldwide, has developed a fully functional Vpu protein in humans.

Vpu (viral protein u) proteins of the non-pandemic HIV-1 O (outlier) group and the rare N (non-M, non-O) group are either unable to antagonise the antiviral factor "tetherin" or are unable to prevent the transport of CD4, the primary receptor of HI viruses, to the cell surface.

In order to protect themselves against retroviral infections, human cells produce restriction factors that inhibit the highly efficient propagation of the viruses. One of these antiviral factors was discovered by American researchers in 2008 and named "tetherin" because it tethers newly produced virus particles to the cell surface, thereby preventing the further spread of the virus.

Vpu has a twofold effect

Vpu increases the efficiency of the release of viruses in two ways. It not only antagonises tetherin, the HIV-1 M Vpu protein also keeps the primary receptor of the immunodeficiency viruses, CD4, away from the cell surface and prevents released virus particles from binding to the already infected cell.

The researchers also investigated whether the Vpu proteins of SIVcpz isolated from chimpanzees (the direct precursor of HIV-1) can also exert this function. To their surprise, the researchers found that SIVcpz does not use Vpu but another viral protein, namely Nef, to antagonise chimpanzee tetherin.

Enforced change

The tetherin variant found in humans is resistant to Nef because it lacks a stretch of five amino acids that normally interacts with Nef. “Immediately after the transmission of simian immunodeficiency virus SIVcpz from chimpanzees to humans, the virus was unable to switch off human tetherin,” explains Kirchhoff. “Since human tetherin is resistant to Nef, HIV-1 was forced to change to Vpu in order to be able to eliminate this antiviral factor.”

Only the major AIDS pathogen, HIV-1 M, succeeded in executing this process perfectly. The Vpu and Nef proteins of the pandemic HIV-1 O group are unable to antagonise tetherin. Although the Vpu proteins of the very rare N virus group have acquired anti-tetherin activity during their adaptation to humans, they have lost the ability to prevent the transport of the CD4 receptor to the cell surface.

Sauter et al.: “Tetherin-driven adaptation of Nef and Vpu function and the evolution of pandemic and non-pandemic HIV-1 strains”, in: Cell Host & Microbe, Vol. 6, Iss. 5, 409-421, 19.11. 2009, doi:10.1016/j.chom.2009.10.004

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