HIV infection: The strategy of resting cells
NRZ Retroviren
The human immunodeficiency virus has to overcome major obstacles to infect inactive immune cells. DZIF scientists have investigated the defence mechanism of these cells and found indications of a new anti-viral mechanism. This knowledge could help develop more effective therapies against HIV.
Infections with HIV can lead to the life-threatening immunodeficiency syndrome AIDS if left untreated. Meanwhile, thanks to antiretroviral therapies, the virus can be contained in the body of the infected patients so that no pathogens are detectable in the blood. However, a complete cure is not possible because infected but resting immune cells form a virus reservoir which cannot be accessed by the currently available drugs. As the resting immune cells possess mechanisms of defence against HIV, only very few cells become infected, yet this is sufficient for the virus to keep spreading into the body from there. A team of DZIF researchers led by Professor Oliver Keppler from the Max von Pettenkofer-Institute and Professor Oliver Fackler from the Heidelberg University Hospital have examined the obstacles HIV has to overcome to infect resting immune cells. Together with colleagues from the DZIF partner site Gießen-Marburg-Langen, they found indications of a defence mechanism that is different to the previously known cellular barriers against HIV. The scientists report their findings in the journal PNAS.
In the human body, HIV particularly infects important cells of the immune system called CD4 T cells. It replicates by transcribing viral RNA into the DNA of the infected cell. This DNA is then integrated into the host cell genome, where it can be translated into new viruses. Resting, i.e. inactive CD4 T cells, defend themselves against HIV with the help of an enzyme called SAMHD1 which, as Keppler and Fackler had already shown in previous studies, inhibits the transcription of viral RNA to DNA by removing and splitting the DNA building blocks. “Many investigated monkey viruses—simian immunodeficiency viruses (SIV), which are considered to be the origin of HIV—can render this enzyme ineffective with the help of a so-called Vpx protein; this leads to a breakdown of SAMHD1 in the cell,” says Keppler. “HIV-2, the ‘little brother’ of HIV-1, the most frequent cause of AIDS in the world, also possesses a Vpx protein.”
The scientists made a surprising discovery when they wanted to get to the bottom of this mechanism: Vpx proteins from SIVs, which had been isolated from less frequently investigated monkey species, had no effect SAMHD1, yet were able to increase the rate of HIV infection in resting CD4 T cells. “Our results suggest that, alongside SAMHD1, another cellular factor must exist with which the cell is able to isolate itself from HIV, which is evidently inhibited by these specific Vpx proteins,” says Fackler. “Interestingly, this mechanism also blocks viral RNA to DNA transcription. But it must have a fundamentally different mechanism of action, because, in contrast to SAMHD1, the number of DNA building blocks in the cell is not affected.” Consequently, the scientists consider it to be potentially even more important than SAMHD1.
These findings not only bring new insights into the biology of CD4 T cells with regard to HIV infection, but they could also be medically important. All HIV patients have a virus reservoir in resting CD T cells, but the size of the reservoir differs. Correspondingly, there are large differences between the patients as to how rapidly and strongly the virus spreads again from the reservoir, e.g. after discontinuation of drug treatment. A better understanding of this new defence mechanism could help to therapeutically reduce the viral load in this reservoir.
