V. Biology of HIV
HIV (human immunodeficiency virus) belongs to a class of viruses known as retroviruses, which contain RNA (ribonucleic acid) as their genetic material. After infecting a cell, HIV uses an enzyme called reverse transcriptase to convert its RNA into DNA (deoxyribonucleic acid) and then proceeds to replicate itself using the cell's machinery.
There are two types of HIV: HIV-1 and HIV-2. HIV-1 is the predominant virus that causes AIDS worldwide. HIV-2 is largely confined to West Africa. Unless specified otherwise, HIV generally refers to HIV-1.
Within the retrovirus family, HIV belongs to a subgroup known as lentiviruses, or "slow" viruses. Lentiviruses are known for having a long time period between initial infection and the beginning of serious symptoms. This is why there are many people who are unaware of their HIV infection, and unfortunately, can spread the virus to others.
Similar versions of HIV infect other nonhuman species, such as feline immunodeficiency virus (FIV) in cats and simian immunodeficiency virus (SIV) in monkeys and other nonhuman primates. Like HIV in humans, these animal viruses primarily infect immune system cells, often causing immune deficiency and AIDS-like symptoms. These viruses and their hosts have provided researchers with useful, although 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. Evidence indicates that HIV may enter and exit cells through special areas of the cell membrane known as 'lipid rafts' (more info). 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 2,000 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 genes, gag, pol, and env, contain information needed to make structural proteins for new virus particles. The gag gene codes for a precursor protein that can be cleaved by the viral protease into four smaller proteins: p24 (capsid), p17 (matrix), p7 (nucleocapsid), and p6. The pol gene codes for a precursor protein that contain four enzymes: protease, integrase, RNase H, and reverse transcriptase. The env gene codes for a protein called gp160 that is broken down by the viral protease to form gp120 and gp41, the components of Env.
Six regulatory genes, tat, rev, nef, vif, vpr, and vpu, contain information necessary to produce 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. Recently, researchers discovered that Vif (the protein encoded by the vif gene) interacts with an antiviral defense protein in host cells (APOBEC3G), causing inactivation of the antiviral effect and enhancing HIV replication. This interaction may serve as a new target for antiviral drugs.
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. Three enzymes 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+ 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 co-receptor. 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. The Food and Drug Administration (FDA) has approved one of the so-called fusion inhibitors, T20, for use in HIV-infected people.
Studies have identified multiple co-receptors for different types of HIV strains. These co-receptors are promising targets for new anti-HIV drugs, some of which are now being tested in preclinical and clinical studies. Agents that block the co-receptors are showing particular promise as potential microbicides that could be used in gels or creams to prevent HIV transmission. 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 co-receptor usage expands in approximately 50 percent of patients to include other receptors, notably a molecule called CXCR4. Virus that uses CCR5 is called R5 HIV and virus that uses CXCR4 is called X4 HIV.
Although CD4+ T cells appear to be the main targets of HIV, other immune 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.
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. A few antiviral drugs approved by FDA for treating people with HIV infection work by interfering with this stage of the viral life cycle.
The newly made HIV DNA moves to the cell's nucleus, where it is integrated into the host's DNA with the help of HIV integrase. HIV DNA that enters the DNA of the cell is called a provirus. Several drugs that target the integrase enzyme are in the early stages of development and are being investigated for their potential as antiretroviral agents.
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 (see below).
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, also may enhance transcription by inducing the secretion of cytokines.
After HIV mRNA is processed in the cell's nucleus, it is transported to the cytoplasm. The protein encoded by the HIV's rev gene is critical to this process (more info). 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 proteins and genomic RNA gather inside the cell and an immature viral particle (pink/red in the picture above) 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 precusor proteins (gag and pol) that make up the immature viral core are now cut into smaller functional proteins by the viral protease. This step results in infectious virions. Drugs called protease inhibitors interfere with this step of the viral life cycle. FDA has approved a few such drugs.