Steps in Replicating HIV
The replication of HIV within the body occurs in a predictable sequence of nine steps:
- Attachment/Entry: The virus attaches to the human cell and enters
- Reverse Transcription and DNA Synthesis: Viral RNA is transcribed to DNA and replicated
- Transport to Nucleus: The new DNA moves into the nucleus
- Integration: The new DNA is integrated with the host cell's DNA
- Viral Transcription: New copies of the viral RNA are produced.
- Viral Protein Synthesis: Viral proteins are produced.
- Assembly of Virus: Components of the virus gather near the cell membrane and form by a 'pinching' action of the membrane.
- Release of Virus: The new virus "buds" off from the host cell
- Maturation: Long strands of viral RNA and protein are cleaved into smaller segments by proteases.
1. Attachment/ Entry of HIV into cells. Infection typically begins when an HIV particle, which contains two copies of the HIV RNA, encounters a cell with a surface molecule called cluster designation 4 (CD4). Cells with this molecule are known as CD4 positive (CD4+) cells.
One or more of the virus's gp120 molecules binds tightly to CD4 molecule(s) on the cell's surface. The membranes of the virus and the cell fuse, a process that probably involves the envelope protein of HIV.
Although CD4+ T cells appear to be HIV's main target, other immune system cells with CD4 molecules on their surfaces are infected as well. Among these are long-lived cells called monocytes and macrophages, which apparently can harbor large quantities of the virus without being killed, thus acting as reservoirs of HIV. CD4+ T cells also serve as important reservoirs of HIV: a small proportion of these cells harbor HIV in a stable, inactive form. Normal immune processes may activate these cells, resulting in the production of new HIV virions.
2. Reverse Transcription and DNA Synthesis. In the cytoplasm of the cell, HIV reverse transcriptase converts viral RNA into DNA, the nucleic acid form in which the cell carries its genes. Seven of the 11 antiviral drugs approved in the United States for the treatment of people with HIV infection ? AZT, ddC, ddI, d4T, 3TC nevirapine and delavirdine ? work by interfering with this stage of the viral life cycle.
3. Transport to Nucleus and
4. Integration. The newly made HIV DNA moves to the cell's nucleus, where it is spliced into the host's DNA with the help of HIV integrase. Once incorporated into the cell's genes, HIV DNA is called a "provirus." Integrase is an important target for the development of new drugs.
5. Transcription. For a provirus to produce new viruses, RNA copies must be made that can be read by the host cell's protein-making machinery. These copies are called messenger RNA (mRNA). Production of mRNA is called transcription, a process that involves the host cell's own enzymes. Viral genes use with the cell's own machinery to control this process.
Proteins known as Cytokines that are involved in the normal regulation of the immune response also may regulate transcription. Molecules such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-6, secreted in elevated levels by the cells of HIV-infected people, may help to activate HIV proviruses. Early efforts at stopping HIV replication focused on these chemicals. Other infections, by organisms such as Mycobacterium tuberculosis, also may enhance transcription.
6. Viral Protein Synthesis. (Translation) After HIV mRNA is processed in the cell's nucleus, it is transported to the cytoplasm. HIV proteins are critical to this process: for example, a protein encoded by HIV's rev gene allows HIV structural proteins encoding mRNA to be transferred from the nucleus to the cytoplasm. Without the rev protein, structural proteins are not made.
In the cytoplasm, the virus co-opts the cell's protein-making machinery including structures called ribosomes to make long chains of viral proteins and enzymes, using HIV mRNA as a template. This process is called translation.
7. Assembly and
8. Release (budding) of Virus. Newly made HIV core proteins, enzymes and RNA gather at a spot just inside the cell's membrane, while the viral envelope proteins aggregate within the adjacent membrane. An immature viral particle forms and pinches off from the cell. As it "buds", it acquires an envelope that includes both cellular and HIV proteins from the cell membrane. During this part of the viral life cycle, the core of the virus is immature and the virus is not yet infectious.
9. Maturation. The long chains of proteins and enzymes that make up the immature viral core are now cleaved into smaller pieces by a viral enzyme called protease. This step results in infectious viral particles.
Drugs called protease inhibitors interfere with this step of the viral life cycle. As of this writing, four such drugs-- saquinavir, ritonavir, indinavir and nelfinavir-- have been approved for marketing in the United States.
The information above was extracted from a Fact Sheet produced by the National Institute of Allergy and Infectious Diseases (NIAID) , the branch of the