Drugs used to target different stages of the viral life cycle include fusion inhibitors, which inhibit HIV's docking with the immune system cells; non-nucleoside reverse transcriptase inhibitors; nucleoside reverse transcriptase inhibitors; and protease inhibitors.
The blood is composed of the 'red' fluids which carry oxygen and transmit food, fluid, and oxygen to the various parts of the body, including the brain; and the clear lymphatic fluids, which contain the cells of the immune system.
The cells of the immune system include:
It is the CD4 cells that the human immunodeficieny virus infects, shuts down, uses the machinery of to enable HIV to replicate in the body, and sometimes destroys. Without these cells, the immune system cannot respond effectively to an infection because its cells cannot be summoned appropriately to respond to an invasion.
HIV ingested by the macrophages and monocytes is often not destroyed either (see Dennis Blakeslee's [2001] article that is linked to here), and can live latent within the macrophages and monocytes for extended periods, and then reemerge. However, HIV does not seem to harm the macrophages or monocytes.
So long as HIV does not infect the thymus, the thymus can produce new cells for the immune system. However, when the cells in the thymus are destroyed by HIV, it becomes very difficult for the immune system to fight microbes and keep the body healthy.
The stages in HIV infection of the CD4's include:
Stage Three: Docking With the CD4.
The GP120 proteins that spike outwards from the spherical human immunodeficiency virus dock with various receptors on the CD4 cells, particularly the CCR5 receptor on the CD4. HIV may also dock with the CXCR4 receptor on the CD4's in people who have been infected with HIV for some time. HIV cannot dock as well with all CCR5 receptors. People with a mutated CCR5 receptor gene often progress to AIDS more slowly than other people because of HIV's difficulties in docking with these people's CD4's. People who have both CCR5 receptor genes mutated do not seem to progress to AIDS at all! In addition, Medscape/Reuter's Health (reported by David Douglas of Reuters Health on a study by Robert C. Bollinger/Johns Hopkins University School of Medicine, October 15, 2002; Journal of Infectious Diseases)186:1177-1180) reports that people's "Gag-specific T lymphocyte responses during early HIV-1 infection" appear to be associated with a lower virul load set point."
Stage Five: Shutting Off of Intercellular Communication and Assuring that No Other Copy of the Virus Will Infect the Same Cell.
The tat protein of HIV shuts down many of the cytokines that the CD4 uses in intercellular communication, making it difficult for the cytotoxic killer cells, the suppressor T cells, and the B cells to respond to the infection. Additional tat proteins are released into the bloodstream, where they stimulate additional CD4 cells, so that these can be infected by the growing population of viruses (according to Blakeslee [1999], who is linked to here). According to a recent report in Medscape, "Tat and Rev are absolutely essential for HIV replication," argues Dr. Bryan R. Cullen--of Duke University Medical Center in North Carolina; "So, when we eliminate their expression, the virus is no longer able to replicate itself." Cullen and a colleague, Dr. Glen A. Coburn, are hoping to use small pieces of double-stranded (ds) RNA to block the expression of the HIV proteins TAT and REV. (from 2002; J Virol 76:9225-9231; reported October 21, 2002 in Medscape/Reuters Health, New York.)
The CCR5 coreceptors on the CD4 are shut down by another protein in HIV, nef, which migrates back into the CD4 cellular membrane after the virus has entered the CD4. This prevents additional viruses from entering the CD4 cell. Moreover, proteins from the invading HIV are often not displayed on the receptors as a result, which of course makes it difficult for other immune system cells to find and destroy the infection.
Stage Six: Reverse Transcription of HIV's RNA to DNA That Can Use the Cellular Machinery to Reproduce Itself.
Once inside the CD4, the HIV rests in the cytoplasm, where it uses its reverse transcriptase enzyme to convert its RNA to DNA. Non-nucleoside analog reverse transcriptase inhibitors are used to target this stage of the viral life cycle. Unfortunately, resistance to the Non-nucleoside drugs is common, though these drugs can supplement other drugs, according to Montagnier (2000) Virus.
Stage Seven: Integration of HIV's Newly-Made DNA Into the CD4 DNA in the Nucleus.
The manufactured HIV DNA then moves into the CD4's nucleus, and with the help of HIV's enzyme, integrase, splices with the CD4 DNA in the nucleus, so that it can access the CD4 cell's protein-making machinery to make new viral proteins. All viruses, of course, must use other cells' protein-making machinery!
Nucleoside analog reverse transcriptase inhibitors, such as AZT, are used to target this stage of the viral life cycle, and are, at least initially, very effective. Although some believe that thymidine analogue NRTI's are linked to the loss of some important fat mass--one aspect of wasting--in HIV patients, data in this area is still inconclusive according to Graeme Moyle (2002, Medscape), though there may be some advantage in switching away from the thymidine analogue NRTI's to drugs such as Abacavir! Abacavir is an NTRI that is not a thymidine analogue NRTI. 3TC, commonly taken with AZT, and which enhances AZT's effects reportedly (according to Montagnier, 2000, "[m]utations [in HIV] resulting in resistance to 3TC actually make the virus sensitive to AZT"), is also considered less toxic.
Some NRTI's have also been associated with Anemia, according to Alexandra Levine (2002; reported in Medscape/Reuters Health), so testing and treatment for anemia may be needed with NRTI's. NTRI's may impair the mitochondrial cellular energy, according to my reading of Montagnier's (2000) Virus.
NRTI's are capable of penetrating the brain barrier and also the placenta. One problem though is the risk of side effects from AZT.
According to Darbyshire J, Foulkes M, Peto R, Duncan W, Babiker A, Collins R, Hughes M, and Peto T, Walker A.(2002; "Immediate versus deferred zidovudine (AZT) in asymptomatic or mildly symptomatic HIV infected adults" [Cochrane Review] The Cochrane Library, Issue 2 [Oxford: Update Software]), cited in Medscape/Reuters Health, 2002, starting therapy with AZT immediately (rather than delaying it) "halved the rate of disease progression" in the first year, but, after six years, persons in the authors' study who had deferred AZT an average of just over two years experienced benefits equal to those who had started AZT immediately. Montagnier (2000) notes that AZT seems to need phosphate molecules to become activated, something only present when lymphocytes strongly activated, for example, in later disease stages. Thus AZT may not be that effective in early HIV. Montagnier, in Virus, however, cites the effectiveness of AZT during the last SIX weeks of pregnancy followed by TWO more weeks for the newborn, because AZT penetrates the placenta barrier. Montagnier cites a French-U.S. study in which AZT taken alone appeared to reduce mother-to-enfant transmission of HIV (I think type B HIV, the type prevalent in Europe and the Americas) 3 to 4 times when taken as described! (I have questions about taking AZT alone, though, and would also look into nutritional supplements, and medicines that combat the side effects of AZT! Also, in a study reported in Medscape (2003), 20% of women given a single dose of Nevirapine developed a resistant variety of HIV--though the resistant mutation disappeared within 12 to 24 months; however the resistant HIV can be passed through breast milk according to Medscape News (February, 2003)--I think that HAART might reduce the possibility of HIV's mutating in response to AZT and becoming less effective though of course, HAART might be less effective later if stopped after pregnancy and and restarted a short time after.) Medscape/Reuter's Health (2002) reports that:
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AIDS activists continue to work to make AZT more readily available to pregnant women in South Africa, while South Africa's Medicines Control Council (MCC)'s Dr. J. Levin reports that AZT may be less effective than the most intensive triple therapy (HAART) regimens. Various studies of the use of AZT to prevent vertical transmission in Africa have shown little difference between the longer term AZT regimens (beginning at thirty-six weeks gestation) and the shorter term AZT regimens (beginning two weeks before delivery or even at the onset of labor; in some cases AZT was also provided to the infant for 72 hours after birth). Other studies (in Thailand) reported that AZT taken prenatally from 36 weeks to birth was associated with lower birth weights, wherease AZT begun after the last two weeks of pregnancy was not. Unfortunately, as noted above, resistance is becoming a major problem with these regimens according to Medscape and AIDS Read 12(7):288-292 (2002 Cliggott Publishing, Division of SCP Communications). Andrea Kovacs of Medscape/Reuter's Health asks about the health policies we should make as a result of resistance to AZT/nevirapine-- "especially in areas of the world where nevirapine is, essentially, the only available regimen to prevent perinatal transmission: Should nevirapine use be curtailed and limited to the perinatal setting so that increased resistance does not develop in the population? If mutant variants develop in a large percentage of the population and are transmitted between sexual partners, the usefulness of this regimen will be severely diminished." |
Stage Eleven: Cleaving
The newly-made HIV is not infective when it first leaves the CD4. It matures only after it leaves the CD4, by using its protease enzyme to cleave the long protein chains into shorter chains that are infective. Protease inhibitors are the powerful anti-viral drugs that target this stage of HIV infection. According to Montagnier (2000; Virus), protease inhibitors, though they do not penetrate the blood-brain barrier and thus may leave some infection latent there, can reduce viral load by 100-to-1000 times, and kill essentially all of the virus that is in the bloodstream (outside of the brain) that is currently not infecting cells--if I read him right!
Dr. J r me Estaquier of the Institut Pasteur in Paris, France and colleagues reported in a recent article that "addition [into a treatment regimen] of the protease inhibitor saquinavir at a concentration of 0.2 M decreased HIV-mediated CD95 expression" [one path to apopstosis that t-cells undergo in the presence of HIV], and also seemed to decrease related cell death. However, addition of saquinavir or indinavir "at concentrations of 10 M induced a loss of mitochondrial membrane potential," and also seemed to induce cell death. 2002; J Virol 76:5966-5973; reported in Reuters Health Information 2002. (?2002 Reuters Ltd.)
Though protease inhibitors offer hope, and may cause HIV to mutate in ways that make it less able to infect the thymus, these drugs have many side effects, too, including possible thickening of the coronary walls, according to Dr. Shenghan Lai who, with his colleagues at Johns Hopkins, studied patients on stable antiretroviral therapy over time (2002; Journal of Acquired Immune Deficiency Syndrome 30:306-310; reported in Medscape/Reuter's Health, July 24, 2002, by Faith Reidenbach). Dr. Lai advised that patients "taking PIs should be evaluated by echocardiography regularly--every 6 months--for changes in their cardiac structure and function."
Thanks to its proteins, such as tat, HIV replicates rapidly from the moment it enters the body, generally overwhelming the immune system, perhaps very early in infection!
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* From Myron S. Cohen, MD. (2001). Further Refinements in Antiretroviral Regimens to Prevent Vertical Transmission of HIV. Abstracted in Medscape Portals, Inc. Chicago, Sunday, December 16, 2001. Reporting on: Thistle P, Arbess G, Dayan R, et al. (2001). Efficacy of an ultra short zidovudine (ZDV) regimen in the prevention of perinatal HIV transmission in Zimbabwe. Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy; December 16-19, 2001; Chicago, Illinois.
Also: Nutrition may play a role in preventing transmission, particularly vitamin A supplements, according to D. N. Burns, G. Fitzgerald, and R. Semba, et. al. (Reported in Medscape's Medline at Reuter's Health, August, 1999).