HIV VIRUS AND INFECTION

HIV VIRUS AND INFECTION
A. HIV virus
The HIV virus belongs to the retrovirus family where the genetic material consists of an RNA molecule. I should say HIV viruses because there is more than one strain of HIV. The more common being HIV1 and HIV2. You will see at the end that the diversity of this virus makes AIDS treatment very difficult. It has an outer lipidic bilayer envelope taken from the cells it infects. This envelope contains spikes which are glycoproteins involved in the recognition and infection of the cells, specially a glycoprotein called gp120. I will come back later on the mechanism of infection. The inner protein coat juxtaposes the outer envelope. Deeper into the virus are the core proteins which surround the single stranded RNA and the reverse transcriptase. This enzyme plays a key role in the infection process.

B. Target cells The target cells of the HIV virus are the lymphocytes T helpers. These cells express a membrane protein called CD4. (Cluster of differentiation #4). This protein is usually involved in the recognition of antigens in association with the molecules of the MHC (Major Histocompatibilty Complex), at the membrane of the APCs cells (Antigens presenting cells); macrophages. But in the case of HIV infection, it is also a receptor for the gp120 glycoprotein of the HIV virus. CD4 also is also expressed at the surface of macrophages (especially in lungs and brain). I am using this figure to comment the target cells to show you how the T Helpers cells are in the center of the immune system. They participate in the cell mediated response but are also involved in the regulation of the humoral response. Then before more explanations, you can see already see how their death can terribly affect the entire immune system.

C. Mechanism of HIV infection
Let's take now a closer look on the life cycle of the HIV virus and on its mechanism of infection. Remember that the binding between HIV and T Helpers is mediated by 2 proteins. The gp120 at the surface of HIV and the CD4 at the surface of T Helpers. CD4 being the ligand for gp120.

1. The first step of the infection consists in the binding of gp120 to CD4. Once the HIV virus is attached to the T Helpers, it fuses with the plasma membrane of the T Helpers and releases its genetic material, single stranded RNA into its host.
2. Once the viral RNA is released into the cytoplasm of the T Helpers, the viral RNA Reverse Transcriptase transcripts the RNA into DNA. We now have an RNA-DNA hybrid molecule. The viral RNA is then degraded by a T Helpers RNAse. The remaining DNA serves as a template for the synthesis of a complementary DNA strand. We now have a double stranded DNA molecule.
3. The double stranded DNA then migrates into the nucleus of the host. It then integrates the genome of the host. This incorporated form of virus is called provirus. At this stage the virus is non infectious. It is in a latent form. This stage can last several months. It is why the apparition of antibodies against the virus I not immediate after infection. The immune system has to wait for macrophages to present the viral antigens as you will see later.
4. The proviral genes are then transcribed into RNA using the host machinery transcription. This RNA can be divided into 2 parts. One part is mRNA and serves as template for the translation of viral proteins and the other part is the viral RNA which will be the viral genetic material.
5. The final step consists in the RNA packaging, meaning assembly of viral RNA and viral protein to form a new virus. You can see that the host plasma membrane is used to form the outer envelope of the virus.
6. New viruses are then release into the extracellular fluid and will infect other cells. This budding of new viruses will also potentially kill the infected cells. At this point I would like to introduce a new concept (fig 14-51 molecular cell biology book). The concept of formation of syncytium. As you can see on this figure, before releasing new viruses, the membranes of the T helpers express the viral glycoproteins. One of them being the gp120. At this stage, the infected T helpers cells can fusion with uninfected T Helpers cells via the binding between the gp120 expresses on infected cells and the CD4 expressed on uninfected cells. This fusion forms a syncytium (multinucleate cytoplasm). A syncytium can involve several T Helpers cells and is lethal for the cells involved. There are then 3 ways for the virus to weaken the immune system.