HIV and AIDS
Doubly resistant when at rest
To successfully infect resting immune cells, Human Immunodeficiency Virus (HIV) must overcome several hurdles. An international research team has identified a new restriction mechanism, which may have implications for therapy.
If left untreated, HIV infection inevitably leads to AIDS, a life-threatening acquired immunodeficiency syndrome, which essentially disables the immune system. HIV is an RNA retrovirus, and antiretroviral therapy (ART) now makes it possible for AIDS patients to control proliferation of the virus sufficiently to keep the numbers of viral particles in the bloodstream below the limits of detection. However, it is not possible to cure the disease, because the virus can persist in resting immune cells. These cells are not accessible to current treatment regimes, and thus form a reservoir from which the virus can re-emerge upon cessation of ART. Resting CD4+ T-cells are largely refractory to HIV because they express so-called restriction factors that limit replication. However, the virus does manage to establish itself in a small fraction of such cells, which can account for the rise in the numbers of circulating virus observed when ART is discontinued. Virologists led by Professor Oliver Keppler of LMU‘s Max von Pettenkofer-Institute and Professor Oliver Fackler at Heidelberg University Hospital have been studying how HIV manages to circumvent the restriction on its replication in resting immune cells. Their latest investigation has uncovered a host-cell defense mechanism that differs from other known cellular barriers to HIV infection. The new findings have been published in the journal PNAS.
HIV infects lymphocytes called CD4+ T-cells, which play an important role in initiating immune responses. Infection of activated CD4+ T-cells is followed by “reverse transcription” of the single-stranded viral RNA into double-stranded DNA. This is then integrated into the cell’s nuclear DNA, and RNA copies are subsequently synthesized that allow the formation of new virus particles, which ultimately kill the cell. In inactive, resting CD4+ T-lymphocytes, on the other hand, reverse transcription of the viral RNA is effectively blocked by the enzyme SAMHD1. As Keppler and Fackler demonstrated in an earlier study, SAMHD1 can do this by destroying the nucleotide building blocks, called dNTPs, required for viral DNA synthesis. “Many of the Simian Immunodeficiency Viruses (SIV), which infect other non-human primates – and from which HIV originates – are able to block the action of this enzyme with the help of their so-called Vpx proteins. Binding of Vpx to SAMHD1 leads to the destruction of the latter in the cell nucleus,” explains first author Dr. Hanna-Mari Baldauf . “HIV-2, a cousin of HIV-1, the latter responsible for the AIDS pandemic, also possesses such a protein.”
When Keppler and his colleagues set out to probe the effects of Vpx proteins from SIVs on the susceptibility of resting CD4+ T-cells to HIV infection, they made a surprising discovery: Although Vpx proteins encoded by SIVs isolated from less well-studied monkey species failed to trigger degradation of human SAMHD1, they nevertheless boosted the rate of infection of resting CD4+ T lymphocytes by HIV-1. “These results suggest that, in addition to SAMHD1, there is a second host factor that restricts HIV proliferation in resting cells, which is inhibited by these specialized Vpx proteins,” Keppler says. “Interestingly, this second mechanism also blocks reverse transcription of the viral RNA into DNA. But it must act in a fundamentally different fashion because, unlike SAMHD1-degrading Vpx proteins, it has no effect on the levels of dNTPs present in cells. For this reason, the researchers believe that it may be an even more important restriction factor in resting T-cells than SAMHD1.
The new findings not only provide new insights into the biology of CD4+ T-lymphocytes in the context of HIV infection, they may well also have clinical relevance. Resting CD4+ T-cells serve as a virus reservoir in all HIV patients, but the size of the reservoir varies greatly from one individual to the next. Consequently, there are large differences between patients with respect to how long it takes the virus to rebound and how severe the ensuing relapse becomes. Understanding the nature of the newly discovered defense mechanism could perhaps point to ways of reducing the size of the viral reservoir.´