Drugs and HIV Evolution

This lecture was conducted by Dr.Bisola 0 0jikutu MD M.P.H Director of the Office of International Programs Division of AIDS, Harvard Medical School,She working has a infectious disease specialist ,concentrating on AIDs disease.She talks about HIV Drugs and HIV Evolution (how HIV got resistant against hiv drugs) and various anti-retroviral drugs, such as AZT,Protease inhibitor and HAART and its mechanism ,which had been used to prevent HIV infection. She also tells how Hiv became resistant to these drugs and concludes with latest HIV drug MARAVIROC and how it might prevent HIV infection


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Most people who are infected with Hiv virus will develop AIDS, The Disease is caused by decrease in Helper T cells count and increase in viral level. Once they develop Aids the Patient will have opportunistic infection. And eventually leads to death.To stop the disease the viral replication should stopped.


Aids infection was first noticed in 1981 and virus was Cultured 1983 .In 1985 commercial test done to detect Hiv antibody, After 6 years medication for HIV is found,The Medication was called AZT (azidothymidine), so what is AZT .


AZT
AZT is a similar analog of thiamine, which is building block of DNA.Difference between AZT and thymine is that AZT has azide side chain rather than hydroxyl chain of thyimidine.

History of AZT
Back in 1960s AZT was synthesized for treating cancer, but it Was unable to prevent cancer, so it was put is shelf, and When HIV came researchers thought "y don't we try this drug for treating HIV”.

Mode of Action of AZT

Generally HIV RNA reverse transcribed to a growing strand DNA, During reverse transcription nucleotides bind to this Growing strand of DNA,When AZT comes in, it looks like a nucleotide ,and binds to the hydroxyl group, But it has azide side chain which blocks further extension of the chain because of this other nucleotides cannot bind to it.

AZT Clinical trial

In Phase 1 AZT clinical trial, they had given AZT to HIV patients for six weeks, they found significant increase of T-helper cells in patient. In phase 2 trials AZT was compared to placebo(a inactive drug that generally used for comparison) In this patients with AZT had low proportion of opportunistic infection than people who had taken placebo.The striking thing in trial is mortality rate, In treatment group who took AZT 1 in 145 people died,but in placebo group 16 out of 137 people died. After 7 months researchers halted the Trial and unblinded it(now patients and researchers now know which drug they are taking) and because of the striking result everybody started to have AZT .The problem with drug was there was increase in Viral level after 22 weeks, that is HIV got resisted to this drug after 22 weeks.

AZT Resistance
The reason behind the HIV got resistant against AZT is that ,when HIV RNA is reverse transcribed to the growing DNA strand,Reverse trascriptase makes lot of errors,so in patients blood we can see lot mutant HIV Virus,so when AZT is given to patients it lowers the amount virus in the blood, But the virus is still replicates it doesn't lowers enough,When you keepon giving the drug ,under the selective pressure HIV virus starts developing more resistant virus.



Protease Enzyme
When HIV buds from the cell, it is not in the matured form,protease enzyme cleves the this unmatured protein in several places so the unmaturatured protein undergoes confirmation changes to make matured HIV virus

Mode of Action of Protease inhibitor
When protease inhibitor enters into cell , The inhibitor bind to the active site in protease enzyme,because of this protease enzymes is unable to cleave the proteins,which inturn result on-maturation of HIV virus

HAART therapy:
Two drugs won't for very long in preventing HIV, So if u give three dugs (2 of AZT type+1 protease inhibitor) we can see sustained decrease in HIV virus in blood and increase in T-helper cells level

CCR5
Researcher found that Certain people are not affected by HIV though they had repeated exposure to HIV virus. One hypothesis researchers told These people would have some genetic mutation in immune system, which stops HIV to entering into the cells. Researchers found that these people had small CCR5 receptor (chemokine co-receptor) in T-helper cells, which makes HIV not able to enter the cell. This makes to good drug target,If we able to inhibit CCR5 receptor then HIV virus will be unable to enter the cell.

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