HIV/AIDS prevention and treatment BTY328: Virology

Monitoring the progress of HIV infection and AIDS

Routes of HIV infection The three main transmission routes of HIV are sexual contact, exposure to infected body fluids (eg blood) or tissues, and from mother to fetus or child during perinatal period. It is possible to find HIV in the saliva, tears, and urine of infected individuals, but no recorded cases of infection- risk of infection is negligible?.

Routes of HIV infection

HIV transmission Typical condom use reduces the risk of heterosexual HIV transmission by approx. 80% over the long-term, although the benefit is higher if condoms are used correctly on every occasion (upto 98-99%). Where one partner is infected and with consistent condom use, HIV infection rates for the uninfected partner are below 1% per year. Randomized controlled trials have shown that male circumcision lowers the risk of HIV infection among heterosexual men by up to 60%.

Needle stick injury Health care workers: needles, scalpels and glass:-careful disposal of to prevent needlestick injuries with contaminated items. Intravenous drug : needle-exchange programmes can reduce the infections caused by drug abuse. Estimated that 20% of infections in Africa are do to iatrogenic effects (unscreened blood, poor sterilisation of needles/equipment)‏

Mother to child transmission Transmission can occur mother to foetus During breastfeding: Current recommendations replacement feeding is acceptable, feasible, affordable, sustainable and safe, HIV-infected mothers should avoid breast-feeding their infant. However, if this is not the case, exclusive breast-feeding is recommended during the first months of life and discontinued as soon as possible.

Treatment Since AIDS is asyndrome treatment is often of the opportunistic infections. An ideal drug would excise all HIV provirus from cells DNA, or eliminate all HIV infected cells. If HIV replication can be suppressed long enough, all HIV infected cells will die off. Several strategies for reducing viral host cell invasion and replication...

Nucleoside analogue RT inhibitors (NNTRIs) ‏ Drugs that resemble the 4 nucleosides used to make DNA. e.g AZT nucleoside analogues are RT inhibitors that stop further synthesis the viral genome. the dideoxy- analogues stops RT from joining next nucleoside by 3'-5' phosphodiester bond these drugs have limited effectiveness as a monotherapy because of the toxic side effects, individually they do not delay the onset of AIDS, and HIV becomes resistant to each one.

Non-nucleoside analogue RT inhibitors (NNTRIs)‏ In contrast to NRTIs, NNRTIs are not incorporated into viral DNA but inhibit HIV replication by binding to RT. e.g. Nivirapine this blocks DNA polymerase and stops HIV DNA replication HIV has shown rapid resistance to these drugs and the resistance can often lead to cross- resistance

Protease Inhibitors eg. saquinavir, ritonavir, indinavir, nelfinavir etcsaquinavirritonavirindinavirnelfinavir HIV proteases required late in HIV replication cycle to process precursor GAG and POL polyproteins into mature HIV proteins. The aspartyl protease of HIV cleaves GAG (p55) and GAG-POL (P160) polyproteins into structural GAG protein subunits and three viral enzymes (RT, integrase and protease). At least 15% of people have serious side effects to protease inhibitors, another 15% do not respond at all to protease inhibitors.

Fusion or Entry Inhibitors Maraviroc and enfuvirtideMaravirocenfuvirtide Fusion inhibitor T-20 has been licensed both in the US and in Europe since 2003, but only for use by people who have already tried other treatments (requires injection). A new type of entry inhibitor known as maraviroc was licensed in This drug is known as a CCR5 inhibitor as it blocks the CCR5 co-receptor on human immune cells, preventing HIV from attaching to the cells' surface.

Other drugs in development Integrase inhibitors inhibit the enzyme integrase, which is responsible for integration of viral DNA into the DNA of the infected cell. There are several integrase inhibitors currently under clinical trial- raltegravir became the first to receive FDA October Maturation inhibitors inhibit the last step in GAG processing in which the viral capsid polyprotein is cleaved, thereby blocking the conversion of the polyprotein into the mature capsid protein (p24). Because these viral particles have a defective core, the virions released consist mainly of non-infectious particles. Under investigation, bevirimat ( first isolated from Syzygium claviflorum, a Chinese herb. ) and Vivecon.Syzygium

Combination therapy: HAART HAART allows the stabilization of the patient’s symptoms and viremia. Without treatment, the net median survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype, and the median survival rate after diagnosis of AIDS (treatment is not available) ranges between 6 and 19 months. HAART reduced the death rate from this AIDS by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to about 20 years.

HAART can double life expectancy of HIV+ Without treatment, the net median survival time after infection with HIV is 9 to 11 years, and the median survival rate after diagnosis of AIDS in resource-limited settings where treatment is not available ranges between 6 and 19 months, depending on the study. HAART reduced the death rate from this AIDS by 80%, and raised the life expectancy for a newly-diagnosed HIV-infected person to about 20 years.

Evolving virus- new treatments needed Mutation of RNA viruses results in the rapid evolution of drug-resistant viral quasi species. In an HIV-infected person, about 10.3 x 10 9 virions are produced per day. These have a half life of 5.7 hours and a fixed mutation rate of 3 x per base per replication cycle in an HIV genome of 10 4 base pairs. This means that at least one mutation may occur in each nucleotide of the HIV genome in a day. New treatments continue to be developed and because HIV continues to evolve resistance to treatments and estimates of survival time are likely to continue to change……

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