Bio 311

Sexually Transmitted Diseases

Lecture 5

HIV and AIDS

The following information was taken from AIDS: The Biological Basis by Edward Alcamo, third edition, 2003. Jones and Bartlett Publishers, Sudbury, MA and from The Scientist (2004) volume 18 issue number 2, an issue Titled “HIV Hide & Seek.”

Viruses:

• Are made up of a genome (DNA or RNA) and a capsid (a protein coat that protects the genome from the environment). Some viruses, like HIV, also have an envelope (a lipid bilayer covering the capsid).
• Viruses do not perform energy-generating chemical reactions
• They do not synthesize proteins on their own
• They do not consume food.
• They do not grow.
• They do not produce waste products
• THEY DO REPLICATE, BUT NEED A CELLULAR HOST TO DO SO.
• Viruses can be helical, icosahedral or a combination of these.

Viral Replication:

• Adsorption-Viruses first have to adsorb to the cellular host. That is, they have to attach to the cellular host using very specific cell surface molecules as well as very specific viral molecules.
• Penetration and Infection-Once the virus is in, the capsids are degraded by proteases (host proteins that destroy the protein making up the capsid). The viral genome is now “naked” and can be transcribed by the host’s transcriptional machinery and make more viruses. For HIV, the process is different as explained below.
• Replication can take minutes for some viruses or hours or days for other viruses.
• Massive replication of the virus inside the host cell can lead to the host cell bursting, a process called cellular lysis.

Human Immunodeficiency Virus (HIV)

• In 2003, 3 million people died of AIDS worldwide, making the total deathtoll 32 million worldwide since the early 1980’s. Currently, it is estimated that 40 million people are infected with HIV worldwide. HIV infects T cells, monocytes, macrophages and dendritic cells.
• A person infected with HIV dies of opportunistic infections.
• HIV infection leads to Acquired Immunodeficiency Syndrome (AIDS) because HIV infects and destroys immune cells, leading to a deficient immune system.

• HIV is a virus of 100 nm in size (about 100 times smaller than its host cell). HIV has a genome made up of two single stranded RNA molecules. HIV has a capsid that protects the genome as well as the protein REVERSE TRANSCRIPTASE, an enzyme that is found next to the RNA molecules. The capsid, in turn, is enclosed in a lipid bilayer- the envelope. The envelope is very unique in that it also contains very important recognition proteins that are necessary for HIV to infect the cellular host. The envelope contains the molecules gp120 and gp41.
• The protein gp120 recognizes the molecules CD4 on T cells (see below). Therefore, gp120 is a key component of the HIV envelope to identify the host cell of this virus.
• In addition to CD4, effective adsorption of HIV also relies on the presence of coreceptors, either CXCR4 or CCR5. These coreceptors function primarily to link T cells and HIV.
• HIV can also infect macrophages. In this case, the gp120 molecule binds to the macrophage once at the CD4 site and once at the CCR5 site.
• It has been found that some individuals who have a defective CCR5 gene, that is, a non-existent CCR5 coreceptor, are resistant to HIV. Two copies of the defective genes apparently exist in 1% of Caucasian Americans of Western European descent.
• Other researchers are hunting for different HIV blocking mutations in other groups, mutations that might help explain why some prostitutes in African and Thailand have managed to avoid AIDS despite repeated exposure to HIV.
• After the CD receptor and corecetpor have bound to the gp120 molecule, gp41 pierces the cell memebrane of the macrophage or Tcell and encourages fusion of the viral envelope with the host cell membrane.

Replication of HIV

• Adsorption- gp120 is involved in host cell recognition of CD4 on T cells or macrophages and gp41 is involved in fusion of viral envelope with cell membrane.
• Penetration- The capsid of HIV is destroyed by the host’s proteases. The RNA and reverse transcriptase are released. The reverse transcriptase uses the viral RNA to make double stranded viral DNA.
• Integration-The viral DNA can then be integrated into the host’s genomic DNA. This integraton is carried out by the enzyme integrase. The integration occurs at random sites. The integrated viral DNA is called a PROVIRUS. THIS RESULTS IN HIV INFECTION WITHOUT ANY SYMPTOMS OF AIDS. HOWEVER THE INDIVIDUALS INFECTED ARE CONTAGIOUS BECAUSE T CELLS AND MACROPHAGES ARE PRESENT IN BLOOD AND SEMEN.
• The provirus can escape the body’s defenses when it hides in the host’s genome.
• HIV Activation and Release- The DNA provirus continues to encode HIV particles in the host cell. The protease coded by the HIV genome cuts out functional proteins from the viral “pre-protein.” Once the virus has been assembled into a capsid, the virus buds out of the cell in a process called “budding” and takes along with it parts of the cell membrane. This membrane makes up the envelope of the HIV virus.
• Cell destruction- possible ways in which HIV can kill its host are the following: HIV can punch holes in the cell membrane when the viruses leave. HIV infection can cause cells to cluster because infected cells will express gp120. These cells can then attach to other cells having CD4 receptors. Finally, massive viral replication can lead to the depletion of cellular components and cause desintegration of the cell.

Detection of HIV

• Detection of HIV antibodies in the individual’s serum by ELISA and Western blot.
• Detection of HIV’s DNA or RNA by Polymerase Chain Reaction.

What are the implications of Testing?

When should testing be mandatory?

Current treatment of HIV infection

• Use of drugs that block Reverse Transcriptase, so that RNA can not be converted to DNA. Azidothymidine or AZT is one such drug.
• Protease inhibitors are drugs used to prevent the protein protease from HIV from cleaving the HIV pre-protein into functional protein products.
• Other treatments are also being explored.