F. ANIMAL VIRUS LIFE CYCLES
3. The Life Cycle of HIV
The overall purpose of this Learning Object is to learn how the Human Immunodeficiency virus (HIV) reproduces within certain cells of its human host.
LEARNING OBJECTIVES FOR THIS SECTION
Viruses are infectious agents with both living and nonliving characteristics.
1. Living characteristics of viruses
a. They reproduce at a fantastic rate, but only in living host cells.
b. They can mutate.
2. Nonliving characteristics of viruses
a. They are acellular, that is, they contain no cytoplasm or cellular organelles.
b. They carry out no metabolism on their own and must replicate using the host cell's metabolic machinery. In other words, viruses don't grow and divide. Instead, new viral components are synthesized and assembled within the infected host cell.
c. The vast majority of viruses possess either DNA or RNA but not both.
The Structure of the Human Immunodeficiency Virus (HIV)
HIV (see HIV A, HIV B and HIV C) has an envelope derived from host cell membranes during replication. Associated with the envelope are two HIV-encoded glycoproteins, gp120 and gp41 (def). Underneath the envelope is a protein matrix composed of p17 (def). Inside the virus is a capsid or core made of the protein p24. The nucleocapsid also contains p6, p7, reverse transcriptase (p66/p51), integrase (p32), protease (p10), and 2 molecules of single-stranded RNA, the viral genome (see Fig. 3).
To view further electron micrographs of HIV, see the AIDS Pathology Tutorial at the University of Utah.
The Life Cycle for the Human Immunodeficiency Virus (HIV)
1. Attachment or Adsorption to the Host Cell (def)
Initially, HIV uses a cellular protein called cyclophilin that is a component of its envelope to bind a low affinity host cell receptor called heparin. This first interaction (not shown in the illustrations or animations) enables the virus to initially make contact with the host cell.
In order to infect a human cell, however, an envelope glycoprotein on the surface of HIV called gp120 must adsorbs to both a CD4 molecule (def) and then a chemokine (def) receptor found on the surface of only certain types of certain human cells (see Fig. 1A, Fig. 1B), and Fig. 1C).
Human cells possessing CD4 molecules include:
- T4-helper lymphocytes (def) (also called T4-cells and CD4+ cells)
- monocytes (def)
- macrophages (def)
- dendritic cells (def)
Chemokines are cytokines (def) that promote an inflammatory response by pulling white blood cells out of the blood vessels and into the tissue to fight infection. Different white blood cells have receptors on their surface for different chemokines. The chemokine receptors are now thought to determine the type of CD4+ cell HIV is able to infect.
First, a portion or domain of the HIV surface glycoprotein gp120 binds to its primary receptor, a CD4 molecule on the host cell. This induces a change in shape that enables the chemokine receptor binding domains of the gp120 to interact with a host cell chemokine receptor. The chemokine receptor functions as the viral co-receptor.
This interaction brings about another conformational change that exposes a previously buried portion of the transmembrane glycoprotein gp41 called the fusion peptide that enables the viral envelope to fuse with the host cell membrane. To view an illustration and electron micrographs of HIV, see Fig 1D, Fig. 1E, Fig. 1F, and Fig. 1G .
- Transmission electron micrograph showing envelope and glycoprotein spikes (gp120) of HIV; courtesy of CDC.
- Scanning electron micrograph showing HIV infecting a T4-lymphocyte; courtesy of CDC.
Most strains of HIV are referred to as M-tropic or T-tropic. The gp120 of M-tropic HIV (see Fig. 2) is able to adsorb to the CD4 molecules and the CCR5 chemokine receptors found on CD4+ macrophages, immature dendritic cells, and memory T4-lymphocytes. (M-tropic HIV are also called R5 viruses since they adsorb to the chemokine receptor CCR5.) M-tropic HIV require only low levels of CD4 molecules expressed on the surface of the host cell for infection. M-tropic HIV (def) are thought to spread the infection.These strains appear to be slower-replicating and less virulent than the later T-tropic strains and do not cause the formation of syncytias. HIV initially replicates to high levels within macrophages without destroying them. (The T-tropic HIV (def), found later in HIV infection, are faster-replicating, more virulent, and lead to syncytia formation.)
As time goes by, mutation in the gene coding for gp120 enables some of the HIV to become dual tropic and able to infect both macrophages via the CCR5 chemokine receptor found on these cells, and T4-lymphocytes via the CCR5 and CXCR4 chemokine receptors found on these cells. (Duel-tropic HIV are also called R5X4 viruses since they adsorb to both the chemokine receptors CCR5 and CXCR4.)
Later during the course of HIV infection, most of the viruses have mutated their gp120 to become T- tropic (see Fig. 2) and infect primarily mature dendritic cells and T4-lymphocytes by way of CD4 and the CXCR4 co-receptors found on these cells. (T-tropic HIV are also called X4 viruses since they adsorb to the chemokine receptor CXCR4.) T-tropic HIV require high levels of CD4 molecules expressed on the surface of the host cell for infection. As mentioned, these T-tropic strains of HIV are faster-replicating and more virulent, and cause formation of syncytias and begin the cycles of T4-lymphocyte destruction.
HIV infecting microglia cells in the brain appear to bind to a CD4 molecule and a chemokine receptor called CCR3 found on these macrophage-like cells.
2. Viral Entry into the Host Cell
As mentioned above under adsorption, the binding of a portion or domain of the HIV surface glycoprotein gp120 to a CD4 molecule on the host cell induces a change in shape that brings the chemokine receptor binding domains of the gp120 into proximity with the host cell chemokine receptor. This, in turn, brings about a conformational change that exposes a previously buried portion of the transmembrane glycoprotein gp41 enabling the viral envelope to fuse with the host cell membrane (see Fig. 5 and Fig. 6). After fusion of the viral envelope with the host cell cytoplasmic membrane, the genome-containing protein core of the virus enters the host cell's cytoplasm. (Occasionally the virus enters by endocytosis, after which the viral envelope fuses with the endocytic vesicle releasing the genome-containing core into the cytoplasm.)
3. Viral Movement to the Site of Replication within the Host Cell and Production of a Provirus
During uncoating, the single-stranded RNA genomes within the core or capsid of the virus are released into the cytoplasm. HIV now uses the enzyme reverse transcriptase (def), associated with the viral RNA genome, to make a DNA copy of the RNA genome. (Normal transcription in nature is when the DNA genome is transcribed into mRNA which is then translated into protein. In HIV reverse transcription, RNA is reverse-transcribed into DNA.)
Reverse transcriptase has three enzyme activities:
a. it has RNA-dependent DNA polymerase activity that copies the viral (+) RNA into a (-) viral complementary DNA (cDNA);
b. it has ribonuclease activity that degrades the viral RNA during the synthesis of cDNA; and
c. it has DNA-dependent DNA polymerase activity that copies the (-) cDNA strand into a (+) DNA to form a double-stranded DNA intermediate.
As the cDNA is being synthesized off of the RNA template the ribonuclease activity degrades the viral RNA genome (see Fig. 7A, Fig. 7B, and Fig. 7C). The reverse transcriptase then makes a complementary DNA strand to form a double-stranded viral DNA intermediate (see Fig. 7D).
The double-stranded viral DNA intermediate now enters the host cell's nucleus and inserts into one of the host cell's chromosomes to become a provirus (see Fig. 8A and Fig. 8B). This is accomplished via a viral enzyme called integrase.
After integration, the HIV proviral DNA can exist in either a latent or productive state, which is determined by genetic factors of the viral strain, the type of cell infected, and the production of specific host cell proteins.
The majority of the proviral DNA is integrated into the chromosomes of activated T4-lymphocytes. These generally comprise between 93% and 95% of infected cells and are productively infected, not latently infected. However, a small percentage of HIV-infected memory T4-lymphocytes persists in a resting state because of a latent provirus. These, along with infected monocytes, macrophages, and dendritic cells, provide stable reservoirs of HIV capable of escaping host defenses and antiretroviral chemotherapy.
4. Replication of HIV within the Host Cell
The vast majority of T4-lymphocytes, which are productively infected, immediately begin producing new viruses. In the case of the small percentage of infected, resting memory T4-lymphocytes, before replication can occur, the HIV provirus must become activated. This is accomplished by such means as antigenic stimulation of the infected T4-lymphocytes (def) or their activation by factors such as cytokines (def), endotoxins (def), and superantigens (def).
Following activation of the provirus, molecules of (+) mRNA are transcribed off of the (-) proviral DNA strand by the enzyme RNA polymerase II. Once synthesized, HIV mRNA goes through the nuclear pores into the rough endoplasmic reticulum to the host cell's ribosomes where it is translated into HIV structural proteins, enzymes, glycoproteins, and regulatory proteins (see Fig. 3).
A 9 kilobase mRNA is formed that is used for three viral functions:
a. Synthesis of Gag polyproteins (p55). These polyproteins will eventually be cleaved by HIV proteases to become HIV matrix proteins (MA; p17), capsid proteins (CA; p24), and nucleocapsid proteins (NC, p7). See Fig. 9A and Fig. 9B.
b. Synthesis of Gag-Pol polyproteins (p160). These polyproteins will eventually be cleaved by HIV proteases to become HIV matrix proteins (MA; p17), capsid proteins (CA; p24), proteinase molecules (protease or PR; p10), reverse transcriptase molecules (RT; p66/p51), and integrase molecules (IN; p32). See Fig. 9C and Fig. 9D.
c. During maturation, these RNA molecules also become the genomes of new HIV virions.
The 9kb mRNA can also be spliced to form a 4kb mRNA and a 2kb mRNA.
The 4kb mRNA is used to:
a. Synthesize the Env polyproteins (gp160). These polyproteins will eventually be cleaved by proteases to become HIV envelope glycoproteins gp120 and gp41. See Fig. 9E and Fig. 9F.
b. Synthesize 3 regulatory proteins called vif, vpr, and vpu.
The 2kb mRNA is used to synthesize 3 regulatory proteins known as tat, rev, and naf.
5. Viral Assembly or Maturation within the Host Cell and Release from the Host Cell
Assembly of HIV virions begins at the plasma membrane of the host cell. Maturation occurs either during the budding of the virion from the host cell or after its release from the cell.
- Transmission electron micrograph of HIV budding from a T4-lymphocyte; courtesy of Dennis Kunkel's Microscopy.
Prior to budding, the Env polyprotein (gp160) goes through the endoplasmic reticulum and is transported to the Golgi complex where it is cleaved by a protease (proteinase) and processed into the two HIV envelope glycoproteins gp41 and gp120. These are transported to the plasma membrane of the host cell where gp41 anchors the gp120 to the membrane of the infected cell. See Fig. 10A, Fig. 10B, Fig. 10C, and Fig. 10D.
The Gag (p55) and Gag-Pol (p160) polyproteins also associate with the inner surface of the plasma membrane along with the HIV genomic RNA as the forming virion begins to bud from the host cell.
During maturation, HIV proteases (proteinases) will cleave the remaining polyproteins into individual functional HIV proteins and enzymes such as matrix proteins (MA; p17), capsid proteins (CA; p24), reverse transcriptase molecules (RT; p66/p51), and integrase molecules (IN; p32).. See Fig. 10E, Fig. 10F, Fig. 10G, and Fig. 10H.
a. The Gag polyproteins (p55) will be cleaved by HIV proteases to become HIV matrix proteins (MA; p17), capsid proteins (CA; p24), and nucleocapsid proteins (NC, p7 and p6).
b. The Gag-Pol polyproteins (p160) will be cleaved by HIV proteases to become HIV matrix proteins (MA; p17), capsid proteins (CA; p24), proteinase molecules (protease or PR; p10), reverse transcriptase molecules (RT; p66/p51), and integrase molecules (IN; p32).
The various structural components then assemble to produce a mature HIV virion.
- Transmission electron micrograph of HIV budding from a T4-lymphocyte; courtesy of Dennis Kunkel's Microscopy.
Janet Iwasa, Gaël McGill (Digizyme) & Michael Astrachan (XVIVO). This animation takes some time to load.
Free viruses now infect new susceptible body cells. HIV can also be transmitted by cell-to-cell contact. This can occur when an infected cell with gp120 on its cytoplasmic membrane attaches to CD4 molecules and chemokine receptors on the surface of an uninfected cell. The cells then fuse (see Fig. 11 and Fig. 12).
E-Medicine article on infections associated with organisms mentioned in this Learning Object. Registration to access this website is free.
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