Genetic Engineering and Human Health

Retroviruses

What is a Retrovirus?

The central dogma of biology states that genetic information in DNA is transcribed into messenger RNA (mRNA), which then codes for translation of a particular protein for the purpose of gene expression. The retroviruses are a family of viruses that do not abide by this convention. They were recognized over a hundred years ago as cancer causing agents in animals and named RNA viruses, but it was not until about 1970 that their mechanism began to be understood. ¹⁴ The discovery of an enzyme in the virus particle, now known as reverse transcriptase (RT), was determined to copy the single strand RNA genome of the virus into double stranded DNA, soon after its entry into the host cell. This sequence of events is the very opposite of that proposed by central dogma, and as their transcription appeared to proceed in reverse, they were given the name retrovirus.

The First Human Retrovirus, HTLV-1

In 1980, the first retrovirus that infects humans was discovered and named HTLV-1 (human T cell leukemia virus). ¹⁵ It is estimated that this virus has been a part of the genome of very specific human populations as far back as perhaps one hundred thousand years. Its mechanism of infection is typical of all retroviruses, but it also has some unique characteristics that set it apart from retroviruses found in animals. It targets T helper cells and dendritic cells.

HTLV-1 enters these cells with the help of certain proteins on the cell surface that assist in the binding of the virus envelope to the cell, and then in the fusion of the viral envelope and the membrane of the cell. When the fusion is complete, the RNA genome, which is composed of two identical single-stranded RNA molecules, is released into the cytoplasm. The capsid is removed, and the reverse transcriptase, which comes packaged with the virus, begins copying the RNA genome into a single strand of complementary DNA (cDNA), and then destroys the original RNA genome. The reverse transcriptase then makes a complementary copy of this single DNA strand, producing a double stranded cDNA molecule which contains all the genetic information of the virus. The cDNA molecule then moves into the nucleus of the cell, and with the help of another viral enzyme called integrase (IN), it integrates the genetic material directly into the DNA of the infected cell. Once integration occurs, the viral genome is referred to as a provirus.

The provirus is now capable of producing a lifelong infection in the host, because when the infected cell replicates, the HTLV-1 genome is passed to each of the daughter cells. There are several additional proteins packaged with HTLV-1, one of which is named Tax. It stimulates the cell to replicate, and therefore infected cells propagate more quickly than the non-infected cells, thus producing greater numbers of infected cells. The provirus is now capable of using the cells own RNA polymerase to either make short messenger RNAs (mRNAs) for the purpose of viral protein production, or the entire genome which will become new virus particles. Two of these RNA genomes eventually group together, and along with a set of both viral and cellular proteins, bud through the cell membrane, borrowing a protective envelope as they exit, and leave the cell to begin new infections in neighboring cells.

One limitation to the proliferation of HTLV-1 infection is that the integration of the provirus cannot occur unless the target cell is active, in other words, when it is in the process of replicating its DNA. Since the vast majority of these cells are at rest at any given time, most of them are not susceptible to infection. Also, when infection does occur, the number of viruses produced inside of a cell by HTLV-1 is relatively few, so their exit does not result in cell rupture and subsequent cell death. HTLV-1 therefore establishes what is often referred to as a latent infection. ¹⁶

On the other hand, this low level of activity also benefits the virus. Lower virus count means less viral RNA and viral proteins that can be detected by the host immune system, the killer T cells in particular, so the virus operates relatively undetected. Another advantage the virus has is that when it does proliferate, it is able to disguise several of its proteins to avoid detection when it is in the process of budding from the cell. It also has the ability to spread by direct cell to cell contact without budding at all. In general, because of its ability to hide its activity from the host immune system, it minimizes the response against it, and this a primary reason that this virus has survived successfully for so long.

Although HTLV-1 is not aggressively pathogenic, and most people are not even aware that they are infected, a small percentage of them will eventually experience enough T cell depletion that they become susceptible to development of several types of opportunistic infections. About two percent contract a disease called ATL (adult T cell leukemia), but this normally does not present until forty or more years after the initial infection. ¹⁷ It is believed that this virus, although it is closely related to the much more virulent HIV-1 virus that causes AIDS, has achieved a certain degree of equilibrium with its human host over the course of a hundred thousand years of co-evolution. ¹⁸