Wednesday, September 08, 2004

Allegory explained

First, the city is - you guessed right - the body. The citizens are cells; varied in form and function, working in buildings (organs, if you wish), traveling through a complex road system (the veins). Bacteria, and viruses (Bugs and vermin) are the unwanted strangers; the first category can multiply in 'buildings' (organs), using resources and causing damage. The second category, viruses, must infect cells in order to complete its life cycle.

Fortunately, the immune system is there to control infections. The 'death squads' in the allegory are CD8+ T lymphocytes and NK (natural killer) cells; they recognize infected cells and kill them, limiting the replication of unwanted viruses (or parasites). Decontamination teams are B cells, which are specialized in antibody production. Antibodies are protein that can recognize very specifically any 3D structure formed by molecules. Once coated by antibodies, bacteria/viruses get eaten by 'cleaning teams', macrophages and dendritic cells. The job of these cells is to pick up proteins in their immediate environment, process (digest) them and present fragments to the 'officers', CD4+ T lymphocytes. After a CD4+ recognizes something foreign, it is activated, multiply and organize the immune response against the 'stranger'. Of course, this is a much simplified overview of the immune system, but for now it'll do :)

HIV-1 can infect both CD4+ T lymphocytes and macrophages. These cell types harbor the HIV-1 receptor, CD4, and coreceptors (either CXCR4 or CCR5, chemokine receptors), which interact with gp120, the envelop protein of the virus. Of note, the simple interaction of gp120 with CD4 (in fact, multiple interactions are necessary, there's a certain threshold), is known to cause apoptosis (programmed cell death, or suicide) of CD4+ T lymphocyte; it is believed that it's the principal cause of CD4+ loss associated with AIDS progression. The loss of ‘officers’ impede the normal immune response against other pathogens; nobody dies of AIDS, but of the subsequent uncontrolled infections. HIV-1 is part of the retrovirus family; thus, it integrates its genetic material in the host's genome upon successful infection. Then, it can either go in ‘massive production’ mode, or ‘total invisibility’ mode. The later is the source of HIV-1 resilience. Government weapons are drugs designed by pharmaceuticals targeting various aspects of the virus life cycle; retrotranscription, maturation mediated by the viral protease, and entry. New viruses can’t reinfect new cells when these drugs are present, and infected cells in the ‘mass production’ mode don’t last long (few days for CD4+ T cells to a week or more for macrophages). The problem lies in the ‘dormant’ HIV-1; cells that harbor it don’t die quickly (recent estimations, half-life of 6 months or more, which mean total elimination time of > 70 years, assuming no new reinfection). Drugs have horrid side effects on the long term; patients can’t be on these for their lifetime non-stop. So they have ‘programmed interruptions’ where they stop taking the drugs for 6 months (give or take). In this period, a fraction of the dormant viruses wake up and reinfect the whole system anew. HIV-1 mutates at an alarming rate (2-5 mutations per new infection, estimated); it develop resistance to drugs VERY quickly. Thus, drugs are used in combination to retard resistance, but eventually (with the help of programmed interruptions, or non adherence to the strict multipills regimen two or three times daily) it develops. As we speak, there is NO method to eliminate HIV-1 once it infected successfully.

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