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You are here : Home/ AIDS Zone/ HIV is a Retrovirus

How HIV Causes AIDS - HIV is a Retrovirus

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  HIV belongs to a class of viruses called retroviruses. Retroviruses are ribonucleic acid (RNA) viruses, and in order to replicate they must make a deoxyribonucleic acid (DNA) copy of their RNA. It is the DNA genes that allow the virus to replicate.

Like all viruses, HIV can replicate only inside cells, commandeering the cell's machinery to reproduce. However, only HIV and other retroviruses, once inside a cell, use an enzyme called reverse transcriptase to convert their RNA into DNA, which can be incorporated into the host cell's genes.


Slow viruses

HIV belongs to a subgroup of retroviruses known as lentiviruses, or "slow" viruses. The course of infection with these viruses is characterized by a long interval between initial infection and the onset of serious symptoms.

Other lentiviruses infect nonhuman species. For example, the feline immunodeficiency virus (FIV) infects cats and the simian immunodeficiency virus (SIV) infects monkeys and other nonhuman primates. Like HIV in humans, these animal viruses primarily infect immune system cells, often causing immunodeficiency and AIDS-like symptoms. These viruses and their hosts have provided researchers with useful, albeit imperfect, models of the HIV disease process in people.


Structure of HIV




The viral envelope

HIV has a diameter of 1/10,000 of a millimeter and is spherical in shape. The outer coat of the virus, known as the viral envelope, is composed of two layers of fatty molecules called lipids, taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Recent evidence from NIAID-supported researchers indicates that HIV may enter and exit cells through special areas of the cell membrane known as "lipid rafts." These rafts are high in cholesterol and glycolipids and may provide a new target for blocking HIV.

Embedded in the viral envelope are proteins from the host cell, as well as 72 copies (on average) of a complex HIV protein (frequently called "spikes") that protrudes through the surface of the virus particle (virion). This protein, known as Env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp41 molecules that anchor the structure in the viral envelope. Much of the research to develop a vaccine against HIV has focused on these envelope proteins.


The viral core

Within the envelope of a mature HIV particle is a bullet-shaped core or capsid, made of 2000 copies of another viral protein, p24. The capsid surrounds two single strands of HIV RNA, each of which has a copy of the virus's nine genes. Three of these, gag, pol and env, contain information needed to make structural proteins for new virus particles. The env gene, for example, codes for a protein called gp160 that is broken down by a viral enzyme to form gp120 and gp41, the components of Env.

Six regulatory genes, tat, rev, nef, vif, vpr and vpu, contain information necessary for the production of proteins that control the ability of HIV to infect a cell, produce new copies of virus or cause disease. The protein encoded by nef, for instance, appears necessary for the virus to replicate efficiently, and the vpu-encoded protein influences the release of new virus particles from infected cells.

The ends of each strand of HIV RNA contain an RNA sequence called the long terminal repeat (LTR). Regions in the LTR act as switches to control production of new viruses and can be triggered by proteins from either HIV or the host cell.

The core of HIV also includes a protein called p7, the HIV nucleocapsid protein; and three enzymes that carry out later steps in the virus's life cycle: reverse transcriptase, integrase and protease. Another HIV protein called p17, or the HIV matrix protein, lies between the viral core and the viral envelope


Replication Cycle of HIV

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 carrying 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 binding of gp120 to CD4 results in a conformational change in the gp120 molecule allowing it to bind to a second molecule on the cell surface known as a coreceptor. The envelope of the virus and the cell membrane then fuse, leading to entry of the virus into the cell. The gp41 of the envelope is critical to the fusion process. Drugs that block either the binding or the fusion process are being developed and tested in clinical trials.

Studies have identified multiple coreceptors for different types of HIV strains; these coreceptors are promising targets for new anti-HIV drugs, some of which are now being tested in pre-clinical and clinical studies. In the early stage of HIV disease, most people harbor viruses that use, in addition to CD4, a receptor called CCR5 to enter their target cells. With disease progression, the spectrum of coreceptor usage expands in approximately 50 percent of patients to include other receptors, notably a molecule called CXCR4. Virus that utilizes CCR5 is called R5 HIV and virus that utilizes CXCR4 is called X4 HIV.

Although CD4+ T cells appear to be the main targets of HIV, other immune system cells with and without 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

Cell-to-cell spread of HIV also can occur through the CD4-mediated fusion of an infected cell with an uninfected cell.


Reverse transcription

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. Nine of the 15 antiviral drugs approved in the US for the treatment of people with HIV infection -- AZT, ddC, ddI, d4T, 3TC, nevirapine, delavirdine, abacavir and efavirenz -- work by interfering with this stage of the viral life cycle.


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. HIV DNA that enters the DNA of the cell is called a "provirus." Integrase is an important target for the development of new drugs


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), and production of mRNA is called transcription, a process that involves the host cell's own enzymes. Viral genes in concert with the cellular machinery control this process: the tat gene, for example, encodes a protein that accelerates transcription. Genomic RNA is also transcribed for later incorporation in the budding virion.

Cytokines, proteins 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. Other infections, by organisms such as Mycobacterium tuberculosis, may also enhance transcription by inducing the secretion of cytokines.


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 the rev gene allows mRNA encoding HIV structural proteins 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.


Assembly and budding

Newly made HIV core proteins, enzymes and genomic RNA gather just inside the cell's membrane, while the viral envelope proteins aggregate within the membrane. An immature viral particle forms and buds off from the cell, acquiring 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. 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.






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