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| The Structure and Life Cycle of HIV |
How does HIV evade the immune system so efficiently? Why are so many variants of the virus found in a single patient? Understanding the structure and life cycle of the virus is key to answering these questions and essential to the design of effective treatments.
HIV is an enveloped RNA virus: As HIV buds out of the host cell during replication, it acquires a phospholipid envelope. Protruding from the envelope are peg-like structures that the viral RNA encodes. Each peg consists of three or four gp41 glycoproteins (the stem), capped with three or four gp120 glycoproteins. Inside the envelope the bullet-shaped nucleocapsid of the virus is composed of protein, and surrounds two single strands of RNA. Three enzymes important to the virus's life cycle - reverse transcriptase, integrase, and protease - are also within the nucleocapsid (Fig. 3).
Although helper T cells seem to be the main target for HIV, other cells can become infected as well. These include monocytes and macrophages, which can hold large numbers of viruses within themselves without being killed. Some T cells harbor similar reservoirs of the virus.
Entry of HIV into the host cell requires the binding of one or more gp120 molecules on the virus to CD4 molecules on the host cell's surface. Binding to a second receptor is also required. Ed Berger helped identify this coreceptor. As he compared his results with those of other researchers, it became clear that two different coreceptors are involved in the binding. One, CCR5, a chemokine receptor, serves as a coreceptor early in an infection. Another chemokine receptor (CXCR4) later serves as a coreceptor. That two coreceptors are involved is consistent with previous observations. Viruses isolated from individuals early in an infection, during the asymptomatic phase, will typically infect macrophages in the laboratory, but not T cells (the viruses are M-tropic). Virus isolated from patients later in the infection in the symptomatic phase, will infect T cells (the viruses are T-tropic). It seems that a shift takes place in the viral population during the progression of the infection, so that new cellular receptors are used and different cells become infected.
HIV is a member of the group of viruses known as retroviruses, which share a unique life cycle (Fig. 4). Once HIV binds to a host cell, the viral envelope fuses with the cell membrane, and the virus's RNA and enzymes enter the cytoplasm. HIV, like other retroviruses, contains an enzyme called reverse transcriptase. This allows the single-stranded RNA of the virus to be copied and double-stranded DNA (dsDNA) to be generated. The enzyme integrase then facilitates the integration of this viral DNA into the cellular chromosome. Provirus (HIV DNA) is replicated along with the chromosome when the cell divides. The integration of provirus into the host DNA provides the latency that enables the virus to evade host responses so effectively.
Production of viral proteins and RNA takes place when the provirus is transcribed. Viral proteins are then assembled using the host cell's protein-making machinery. The virus's protease enzyme allows for the processing of newly translated polypeptides into the proteins, which are then ultimately assembled into viral particles. The virus eventually buds out of the cell. A cell infected with a retrovirus does not necessarily lyse the cell when viral replication takes place; rather, many viral particles can bud out of a cell over the course of time.
HIV is transmitted principally in three ways: by sexual contact, by blood (through transfusion, blood products, or contaminated needles), or by passage from mother to child. Although homosexual contact remains a major source of HIV within the United States, "heterosexual transmission is the most important means of HIV spread worldwide today." 2 Treatment of blood products and donor screening has essentially eliminated the risk of HIV from contaminated blood products in developed countries, but its spread continues among intravenous drug users who share needles. In developing countries, contaminated blood and contaminated needles remain important means of infection. Thirteen to thirty-five percent of pregnant women infected with HIV will pass the infection on to their babies; transmission occurs in utero, as well as during birth. Breast milk from infected mothers has been shown to contain high levels of the virus also. HIV is not spread by the fecal-oral route; aerosols; insects; or casual contact, such as sharing household items or hugging. The risk to health care workers is primarily from direct inoculation by needle sticks. Although saliva can contain small quantities of the virus, the virus cannot be spread by kissing.