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HIV origins, subtypes and viral replication
The major topics covered by this lecture are:
Where did HIV come from?...the million dollar question.
Where HIV came from is perhaps not as important as knowing how and when this virus family emerged. Tracking these viruses and how they are evolving helps us to anticipate health care needs, and to design better drugs and hopefully vaccines.
The story surounding the origins of these viruses is filled with controversy, finger-pointing, blame and misunderstanding. It is human nature to look for simple answers to complex issues; to look for a "patient zero" or blame a particular segment of society for being the cause of all their problems. The story of HIV has no simple solution.
"AIDS cannot be explained by a single virus causing a single and continuous epidemic. Instead, worldwide spread is the work of a virus family of types, subtypes, and strains that cause more or less related epidemics. Each member of the family has its own distinctive behavior, and each epidemic runs its own distinctive course." (From J. Gooudsmit. 'Viral Sex: The Nature of AIDS.' 1997)
At least four major groups of theories have been put forward to explain the origins of HIV.
The first two theories have more credibility and are supported by scientific lines of investigation. The other two theories are not backed up by scientific evidence and/or are not widely accepted by the scientific community.
During the 1960's and 1970's there was tremendous upheaval in African countries as they began to win their independence. In particular, the former Belgian Congo became Zaire almost overnight and had to replace Belgian government officials and civil servants with black, french-speaking people in a short period of time. In the 1970's many Haitians travelled to Zaire to fulfill this purpose and to assist training of Zairians. Haitians then returned to Haiti in the late 1970's and soon after many started developing AIDS. It was observed that Haitians living in the US that had not traveled to Africa prior to 1975 did not have problems with HIV.
Up to 400 hundred blood samples from rural Zaire had been stored from an Ebola virus outbreak in 1976 and had been stored in freezers. In 1986 the blood samples were tested for HIV and five were found to be HIV positive. This was probably the worlds first smallest retrospective study. A further test of about 600 bloods from Zairian subjects in 1986 found about the same prevalence rate of HIV as that of 1976; about 0.8%. This showed that HIV probably existed at a low endemic level for a number of years prior to 1976 in Zaire but the the exact date is unclear. Both the nature of isolated rural Africa and social-sexual mixing patterns kept the virus at bay.
From the 1970s on there has been tremendous political change and upheaval in Africa; mass migration, changes in sexual patterns, and so on have allowed the virus the opportunity to emerge into an epidemic form.
SF examiner 2/4/98. "Reseachers find earliest known case of AIDS in Kinshasa clinic."A blood sample from a man who died of AIDS-like symptoms in Zaire in 1959 has been confirmed as being the earliest documented case of HIV. However, earliest does not mean the first. This case is further evidence for an African origin of HIV.
Conspiracy theories are largely based on unfounded fears and have not been borne out by the facts. They include the proposals that HIV was deliberately released from military research labs as an act of germ warfare; HIV contamination of human vaccines (polio, smallpox, hepatitis, tetanus); contamination of monkey kidney cultures used to make polio vaccine; HIV transmission by mosquitoes; UFO's carried HIV to earth.
The germ warfare/CIA conspiratorial theories were advanced by two main camps: the KGB and anti-vivisectionists. They found support in African countries and among other groups who felt blamed for 'starting' the epidemic.
There is no evidence of deliberate or accidental contamination of vaccines. However, the re-use of syringes in developing countries for medical use could have contributed to infections during immunization campaigns. Tests of poliovirus seed stocks, over 20 vaccine lots and sera from 250 vaccine recipients turned up negative. Epidemiology has not linked groups of polio vaccine recipients to AIDS and no monkey (used in vaccine production) has been found to be naturally infected with HIV-1 (Cohen. Science 1992).
The mosquito link was advanced because early ELISA kits reacted with a high false positive rate in people who had malaria. Many children got HIV as a result of blood transfusions for malaria-related anemia and NOT because of mosquito bites.
There's no proof that UFO's brought HIV here!!!
This viewpoint is proposed by Dr.Peter Duesberg of U.C. Berkeley. Despite some pretty heavy duty scientific credentials, Peter Duesberg 's view of AIDS is considered a minority position and unsound by the majority of the scientific community. Despite an overwhelming body of evidence that HIV does cause AIDS and that antiviral drugs help slow disease progression Peter Duesberg seems to ignore the facts.
Duesburg advocates that AIDS is due to 'lifestyle factors' and is a collection of NONINFECTIOUS IMMUNODEFICIENCIES due to abuse of drugs, injesting toxins, poor nutrition and so on.
Duesberg also argues that drugs like AZT are the CAUSE of AIDS rather than a treatment. However, a famous clinical trial referred to as ACTG protocol 076 showed AZT reduced transmission of HIV from pregnant women to children from 25% to 8%.
For a balanced view of Peter Duesberg's claims and the evidence against them see the following article: The Duesberg Phenomenon. J. Cohen. Science 266. Dec 1994; 1642-1649.
To see a picture of HIV click here
To see an animation of the HIV life cycle click here Cells alive
Genes that HIV uses to carry out its life cycle:
The genetic material of HIV consists of 2 copies of single-stranded RNA. The RNA of HIV contains the viral genes necessary for the following viral structures and activities:
All retroviruses have RNA that codes for the same three structural genes. The order of these genes never varies between retroviruses. The genes and their products are as follows:
| GAG | Group antigen gene | makes up the proteins that from the virus'
inner core; a kind of shell |
| POL | The polymerase gene | This part of the viral genetic material carries the instructions for
three critical enzymes that are necessary for viral replication:
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| ENV | The envelope gene | codes for two viral proteins that occur in the outermost coator envelope of HIV. These two proteins are called Gp 41 and Gp 120. These proteins are found in the knobs coating HIV and are used by the virus in docking to host cells with the CD4 marker. |
Long terminal repeats (LTRs) are sequences of similar genetic material that occur either side of HIV's main genes:
LTR- GAG POL ENV- LTR
The LTRs do not code directly for any protein but act to regulate the expression of other viral genes
Unlike most other retroviruses HIV and SIV have 6 other genes involved in regulating 3 main structural genes.
Each regulatory gene codes for a protein that interacts specifically with a 'responsive' element: a short sequence genetic material elsewhere in the genome. The regulatory genes control the rate of viral multiplication.
A brief overview of the 6 regulatory genes of HIV:
| Gene | Main activity |
| tat | tat can boost viral gene expression 1,000 times more than HIV mutants lacking tat. Tat stimulates production of all viral proteins |
| rev | Ensures that the appropriate balance of viral proteins are made throughout the viral life cycle in a coordinated fashion |
| nef | Seems to increase HIV infectivity. Target sequence found in the LTRs. A study of 6 Australian long term nonprogressors infected with HIV from a blood donor remain free of disease 10-14 years later. Their HIV strains all had deletions in the Nef gene (Deacon et al. Science 1995. 270; 988.) |
| vif | necessary for full infectivity |
| vpu | assists viral replication |
| vpr | for efficient budding of virus out of host cells and increased rate of particle release. |
How do antiviral drugs interfere with HIV replication?
Two major enzymes that HIV uses for replication are the current targets of antiviral drugs:
Drug target: Reverse transcriptase (RT)
Activity:The enzyme that HIV uses to copy its genetic material into a DNA copy prior to insertion in the host cell chromosome.
Drugs: AZT and 3TC and other nucleoside analogs act to chemically fool reverse trnscriptase as it attempts to make a DNA copy. An "analog" looks very similar to one of the building blocks used in making DNA. However, the analog does not allow RT to 'join' the building blocks together correctly. The zipper on your jacket has two sets of interlocking teeth that have to fit together perfectly in order for the zipper to work properly. If the match is imperfect then your jacket is pretty useless. Similarly, each copy of the viral DNA must match up correctly in order for it to function. Nucleoside analogs "mess up the viral zipper."
Non-nucleoside reverse transcriptase inhibitors (NNRTI's) also target reverse transcriptase but in a different way from nucleoside analogs. The NNRTI's bind to RT at a different site and distort it so that it can't function properly.
Drug target: HIV Protease.
Activity: The enzyme that HIV uses late in its life cycle to cut HIV proteins into small functional proteins so that they can be incorporated into new viruses. Protease is a general term for any enzyme that can cut up proteins.
Drugs: Protease inhibitors act to block protease from carrying out its activity of being viral scissors. Defective viruses can bud from the cell but hey have lost their infectivity.
For more information on anti-viral drugs go the the link for Project Inform, San Francisco
Which cells are targeted by HIV?
HIV targets two major types of white blood cells that carry a marker on their surface called CD4:
Macrophages: the "big eaters" of the immune system. Normally these cells act to gobble up infectious microbes in the blood and tissues of the body and destroy them before they have a chance to cause infection. Certain bugs like HIV have figured out a way to live inside macrophages without being killed.
T cells or T lymphocytes: these cells are like the conductors of an orchestra and function to keep the immune system in tune. Without these cells the immune system can not communicate effectively and loses the ability to fight off infections that it can normally control.
The CD4 marker is like a doorknob that HIV must turn before it can gain entry into its new home.
Recent evidence indicates that the initial infecting strain of HIV targets macrophages first. These strains are known as M-tropic viruses. The virus multiplies more slowly and steadily in these cells and macrophages are probably a cellular reservoir of infection, allowing seeding of virus around the body.
In the later stages of HIV infection the virus switches targets and invades CD4+ T cells. These strains are called T tropic viruses. At this stage the virus seems to become more agressive and cause 'syncytia" formation of T cells. T cells tend to clump together forming large blobs that can't work properly.
Besides the CD4 receptor other co-receptors are neccessary for efficient invasion of macrophages and T cells. These act like a key in the lock that HIV has to turn to get into the cell. See what these co-receptors look like.
The co-receptor on macrophages is called CKR-5 and is used by HIV early on in infection. Some people have a mutation in the CKR-5 gene which causes this receptor to not be expressed on their cells. These people seem to resist infection with M tropic forms of HIV.
The co-receptor on T cells is called CKR-4 or Fusin and is the receptor that HIV switches to later on in the course of disease. See how this receptor switch works.
The shift in tropism from macrophage to T-cell invading strains means that the virus is further avoiding destruction by the immune system.
