Vpx protein is a viral accessory protein found in certain lentiviruses, playing a significant role in viral replication and host immune system evasion.
Viral Origins and Discovery of Vpx Protein
The Vpx protein is not a universal component of all lentiviruses, but is found in Human Immunodeficiency Virus type 2 (HIV-2) and certain Simian Immunodeficiency Virus (SIV) strains, including those infecting sooty mangabeys (SIVsm). The discovery of accessory proteins like Vpx was a step in virology. These proteins are not part of the virus’s physical structure but perform specialized functions that enhance viral replication and survival.
Phylogenetic studies suggest the vpx gene arose from a duplication of the vpr gene, another accessory protein in primate lentiviruses. This evolutionary divergence is clear when compared to Human Immunodeficiency Virus type 1 (HIV-1), which does not have a vpx gene. While HIV-1 has its own Vpr protein, the functions of Vpr and Vpx are distinct, contributing to differences in how these viruses establish infection.
Researchers observed that Vpx is packaged into the viral particle (virion) through an interaction with a part of the Gag polyprotein known as p6. This packaging ensures that Vpx is present in the target cell immediately upon infection. This allows it to function during the early stages of the viral life cycle to prepare the cell for viral replication.
Enhancing Viral Infection: The Key Function of Vpx
The primary function of the Vpx protein is to enable efficient infection in non-dividing cells, a category that includes macrophages and dendritic cells. These cell types are often among the first to be targeted by lentiviruses upon entering a host. They play a part in the initial establishment and subsequent spread of the infection.
Without Vpx, viruses like HIV-2 and SIVsm struggle to replicate in macrophages and dendritic cells. These cells have intrinsic defense mechanisms that can block the viral life cycle at an early stage. Vpx neutralizes these defenses, allowing the virus to replicate and establish a productive infection in these immune cells, which can then serve as long-lived viral reservoirs.
Studies with SIVmac viruses that have mutated or deleted vpx genes show the importance of the protein. When these modified viruses are used to infect rhesus macaques, the resulting infection is weakened. The animals exhibit lower levels of virus in their blood and a slower progression to disease, demonstrating Vpx’s role in establishing high levels of viral replication in a host.
Targeting Host Defenses: The Vpx Mechanism
The Vpx protein counteracts a host defense molecule known as Sterile Alpha Motif and HD domain-containing protein 1 (SAMHD1). Vpx itself does not have enzymatic activity to destroy this factor. Instead, it functions as a molecular adaptor, bridging SAMHD1 to the cell’s protein disposal machinery. Vpx binds to SAMHD1 and recruits a cellular E3 ubiquitin ligase complex, which includes components like CUL4A and DDB1.
This recruitment hijacks the cell’s protein degradation system. The E3 ligase complex attaches ubiquitin molecules to SAMHD1, a process called ubiquitination. This “tagging” marks SAMHD1 for destruction by the proteasome, a complex that breaks down unwanted proteins within the cell. By orchestrating the degradation of SAMHD1, Vpx removes a barrier to viral replication.
The function of SAMHD1 in an uninfected cell is to limit the resources needed for viral replication. It achieves this by hydrolyzing deoxynucleotide triphosphates (dNTPs), which are the molecular building blocks for synthesizing viral DNA. During the lentiviral life cycle, reverse transcription must occur, where the viral RNA genome is converted into DNA. By depleting the cellular pool of dNTPs, SAMHD1 halts the infection, and Vpx’s degradation of SAMHD1 ensures dNTP levels remain sufficient for this process.
Broader Implications of Vpx Protein Research
The presence of Vpx in HIV-2 and SIV, and its absence in HIV-1, helps explain differences in the diseases they cause. Because Vpx allows for efficient infection of myeloid cells, these cells become reservoirs and contributors to viral load in HIV-2 infection. This contrasts with HIV-1, which must rely on other mechanisms to navigate the restrictive environment in these same cells.
Vpx’s ability to overcome the SAMHD1 restriction has been harnessed as a tool in biomedical research. In gene therapy, scientists use modified lentiviruses as vectors to deliver therapeutic genes to specific cells. The efficiency of this process in cells like hematopoietic stem cells can be low due to defenses like SAMHD1. By incorporating Vpx into these lentiviral vector systems, researchers can improve the success rate of gene delivery.
Studying the Vpx-SAMHD1 interaction has also deepened our understanding of the innate immune system. The discovery of SAMHD1’s role as a restriction factor was illuminated through research on how Vpx defeats it. This work continues to reveal the strategies viruses have evolved to evade host defenses and provides a clearer picture of the interplay between viruses and immunity.