Main focus of our research activities is the understanding of the molecular mechanisms underlying HIV-1 replication. This page represents a summary of the main research projects of our lab. For a more detailed description refer to the Research page.

Structure and function of HIV-1 RNA
A combination of biochemistry, molecular biology and virology is used to study regulatory RNA signals in the HIV-1 genome. In particular, we study the untranslated leader region of the HIV-1 RNA genome that contains signals that regulate RNA synthesis (the TAR hairpin as binding-site for the Tat protein), RNA processing (splicing and polyadenylation) and late viral RNA functions (dimerization and packaging in virions, and subsequent reverse transcription).

Regulation of HIV-1 replication
The focus is on regulation of LTR-mediated transcription of the HIV-1 genome. This analysis includes the functional analysis of the LTR promoter of different HIV-1 subtypes, and the effect on virus replication and host cell tropism, properties that in turn may influence viral pathogenicity. We also study the structure and function of the HIV-1 envelope protein, its biosynthesis, and its role in T-cell infection and dendritic cell-mediated transmission.

Virus evolution
We optimized HIV-1 tissue culture replication to allow the systematic selection of revertant viruses of replication-impaired mutants. This ‘forced evolution’ approach has been instrumental in the dissection of several replication signals, but has also provided fundamental insight into the mechanism of virus evolution. We also study the evolution of drug-resistant HIV-1 variants, and we try to utilize spontaneous virus evolution to select for novel HIV-1 variants with interesting properties (e.g. a leukemia-specific virus).

Antiviral therapy and drug-resistance
Despite the availability of multiple potent antiviral drugs, it still occurs frequently that patients fail on therapy due to the emergence of drug-resistant HIV-1 variants. We study these evolutionary viral escape routes, the mechanism of drug-resistance and the impact on viral replication fitness. We focus on new entry inhibitors, for which we recently identified a completely new resistance mechanism (drug-dependent virus), and for which we will develop new clinical assays. Rogier Sanders will initiate his own research line based on this topic as part of an AMC-Meelmeijer fellowship.

Vaccine studies
The tetracycline HIV-1
We previously demonstrated that the replication defect of attenuated HIV-1 strains is repaired over time by spontaneous virus evolution. We have made an HIV-1 variant of which the replication can be turned on and off at will by simple addition/withdrawal of tetracycline. We are currently testing the properties and genetic stability of this conditionally replicating HIV-1 variant as a putative vaccine strain.
Furthermore, research on the HIV-1 envelope protein is directed towards the design of more stable envelope forms with improved immunogenic properties.

New antiviral therapies
Based on our solid background in RNA research, we study the possibility to combat HIV-1 by means of RNAi. Virus evolution and the appearance of escape variants is a main topic, but we also plan to develop this antiviral strategy into a gene therapy-based treatment for HIV-infected individuals. Furthermore, we study whether HIV-1 is able to suppress the cellular RNAi defense mechanism.

New genetic switches
The tetracycline virus uses the well-known Tet-system for regulation of viral gene expression and regulation. This system is widely used for regulation of gene expression, e.g. in expression vectors and transgenic mice. We argued that our experimental system could be used to select for improved Tet-systems by means of spontaneous virus evolution. The first results of this applied research line have already been published, and we are confident that greatly improved Tet-systems are now within reach.