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A review paper came out in Science last week that changed my perception of HIV and AIDS. The paper discussed what has been learned about HIV and the immune response by studying the natural hosts of Simian Immunodeficiency Virus (SIV). SIV is the virus from which HIV originated. The term “natural hosts” refers to the carriers of the virus that never develop AIDS. “Natural SIV Hosts: Showing AIDS the Door” by Chahroudhi et al. covers the most recent advances in understanding the mechanisms involved in this protection.
Viruses like HIV and SIV are called “lentiviruses” which are a subfamily of the retrovirus family. The prefix “lenti-” means “slow,” because those infected with HIV can carry the virus for years before developing AIDS. The genome of a retrovirus is made of RNA rather than DNA, and once it is inside the cell of it’s host, it is able to use a host enzyme called a reverse transcriptase to make DNA from it’s genome. Another enzyme called integrase then inserts the newly transcribed virus-derived DNA directly into the host’s genome to be copied indefinitely through normal cell division. In contrast, DNA viruses do not incorporate directly into the host genome in order to replicate. It is for this reason that the host cells usually carry retroviral infections for life.
SIV has infected over 40 species of primates in Africa and is a highly replicating virus. Cross-species transmission of a variant of this virus (called SIVcpz) from chimpanzees to humans, likely through improper handling of infected bushmeat, has been attributed to the HIV-1 epidemic in humans. SIVmac in rhesus macaques is attributed to HIV-2. In order to better understand why the virus causes disease in some hosts but not others, it becomes important to study the conditions where the viral load is quite high but active disease is absent. Because it was thought for a while that high levels of HIV cause AIDS, these types of investigations have been long overdue.
The two natural hosts of SIV are African green monkeys and sooty mangabeys. There are research centers in the United States and Europe dedicated to studying the biological processes that occur in these primates when they are infected with SIV. Because the virus does not give these primates AIDS, researchers are able to infect them with the virus and then extensively monitor how their immune systems respond to the initial infection, or the “acute” phase.
What have the researchers found? In the acute phase of both pathogenic SIV and the benign infection in the natural host, infected cells have a short life span, the viral load is high, and the innate and adaptive immune response is highly active. Also in both systems, the primate suffers a significant loss of a type of immune cell called a CD4+ cytotoxic T-Cell that help the immune system kill off infectious agents.
However, once the acute phase has passed, differences arise. Most significantly, the natural host is usually able to quickly regain it’s healthy CD4+ levels. Evidence of active disease is therefore indicated by a decline in CD4+ levels. According to the paper, many mechanisms for this rapid resolution of immune function in natural hosts have been proposed.
One explanation is that, in response to the virus, the natural hosts initiate processes such as programmed death of immune cells and enzymatic damage of RNA. If there are fewer activated immune cells circulating, then there are fewer immune cells to infect. While high viremia is not associated with the development of active disease, the number of infected cells may matter.
A second hypothesis is that a T-cell receptor called a CD3-TCR is down-regulated in the natural host by a viral protein called Nef. CD3-TCR normally binds a T-cell and allows it to be stimulated by antigens. Infected T-cells with low levels of this receptor will be less prone to stimulation, and therefore less prone to chronic immune activation. The pathogenic virus in the non-natural hosts seems to have lost the ability to down regulate CD3-TCR. (Some researchers have considered a clever experiment to help elucidate this further, in which the benign SIV virus is genetically engineered to produce an HIV-like Nef protein to see if that leads the natural host to develop AIDS.)
A process called bacterial translocation is thought to cause chronic immune activation and progression to disease in HIV and SIV patients. Bacterial translocation is when the integrity of a mucous membrane, such as the intestine, is lost and bacteria present there are able to enter the bloodstream. Another difference between the natural host and the pathogenic case is that the natural host’s mucosal tissue integrity is preserved. Researchers think that this may be protecting the natural host from the bacterial translocation associated with active disease.
Interestingly, it seems that the virus is also less likely to affect the tissues of the natural hosts where the immune responses initiate, such as the lymph nodes, which have shown in experiments to retain normal histology. With lower viral loads in such critical locations, it will become easier for the host to recover it’s CD4+ levels after the acute phase of the infection.
Why would the virus have different tissue specificity in the natural host? While the total number of infected T-cells can impact disease progression, it is thought to be even more important which type of T-cell is affected for AIDS to develop. Different types of T-cells are associated with different tissues.
In the natural host, the more expendable T-helper effector memory cells found in the mucusal tissue called are targeted, and in the pathogenic case, the T-helper central memory cells are targeted. T-helper memory cells are located mostly in the lymphoid tissue, are more long lived in the body. If infected, it becomes more difficult for the host to regain healthy CD4+ levels. This has been shown in measurements of CD4+ infected cells in human HIV sufferers; the infection level of the memory cells is usually the highest of all the T-cells infected.
The central memory cells of the natural host also express much lower levels of the main virus receptor called CCR5 that allows the virus to enter the cell. Also, around 7% of sooty mangabeys actually have a mutant form of the gene that codes for the CCR5 viral receptor, making it less expressed on memory cells, and therefore it is less probable that the virus will enter those cells.
Lastly, there is a small percentage of sooty mangabeys that are born with a naturally low level of CD4+ T-helper central memory cells, and instead have another type of immune cell called a DN (double negative) T-cell that acts as a useful substitute. The naturally low level of CD4+ cells combined with another cell type that produces a productive immune response may protect these animals from AIDS.
In light of all the above evidence, it is believed that the natural hosts of SIV have co-evolved with the virus, where the virus is able to replicate but the host does not suffer disease. Low rates of mother to infant transfer of the virus may also be evidence of this co-evolution. And, infants who do acquire the disease from their mothers usually have relatively low levels of viral replication compared to adults.
A noteworthy observation is that there are rare cases of HIV infected humans who exhibit an immune response very similar to the SIV natural host — stable CD4+ T-cell counts despite high viral load — and never develop AIDS. The authors project that this may lead to new insights in treatment of HIV for humans.
Chahroudi, A; Bosinger S, Vanderford T, Paiardini, M. “Natural SIV Hosts: Showing AIDS the Door” Science. 9 March 2012. Vol 335, 1188-1193. doi: 10.1126/science.1217550
African Green Monkey image: http://naturalunseenhazards.wordpress.com/tag/african-green-monkey/