Above: Image © istockphoto.com/sam74100

Did you know? A peptide is a chain of amino acids. A protein is a peptide that is folded and has a defined three dimensional structure. Proper folding is essential for proteins to function properly.According to official estimates, 71,300 Canadians were living with HIV at the end of 2011, representing an increase of 7300 people since 2008. Youth are particularly vulnerable to HIV infection, in part because of risky sexual behaviour and a lack of accurate information on HIV transmission. Between 2008 and 1998, young people between the ages of 15 and 29 accounted for up to 23% of positive HIV test reports.

The good news is that thanks to advances in HIV treatment, infected people living in North America can now expect to live into their early 70s. This is a dramatic increase from just over 10 years ago, when most individuals who had been diagnosed in their 20s could expect to die in their 50s. In particular, HIV drugs have been developed that target the virus at each of the three main stages of its life cycle.

What is HIV/AIDS?

The human immunodeficiency virus (HIV) is the infectious agent that causes acquired immune deficiency syndrome (AIDS). HIV infects T cells, which are a key part of the immune system. HIV can be transmitted through the blood, semen, vaginal fluid and breast milk of an infected person. AIDS develops when the immune system has been damaged by HIV to such an extent that it can no longer protect the body against opportunistic infections, which are infections that take advantage of weakened immune systems.

Fusion and CCR5 inhibitors

Fusion is the first main stage of the HIV life cycle, when the virus attaches to the host cell (the cell of the infected person) and sends its genome (a single stranded RNA) into the cell. For the virus to enter the host cell, a protein on the HIV plasma membrane (cell membrane) called gp120 must interact with two receptors on the plasma membrane of the T cells, CD4 and CCR5. When gp120 interacts with a particular region of the CCR5 receptor, the plasma membranes of HIV and the T cell fuse and the viral RNA enters the cell.

Did you know? Protease is an enzyme that cleaves (divides) proteins into smaller pieces.CCR5 inhibitors work by blocking the interaction between gp120 and CCR5, thereby preventing viral entry. This is a particularly attractive treatment strategy because it deals with the virus before it has even had a chance to enter the host cell. So far, only one CCR5 inhibitor drug has been approved for HIV treatment.

Integration, replication and reverse transcriptase inhibitors

Integration and replication is the stage of the HIV life cycle when DNA is synthesized from RNA, integrating the viral genome into the host DNA so that the replication machinery of the host cell can be used to make more copies of the virus.

Retroviruses, including HIV, have an enzyme called reverse transcriptase that can synthesize DNA from RNA. In humans and many other organisms, RNA is synthesized from DNA and proteins (peptides) are synthesized from RNA (DNA→RNA→Peptide). However, in retroviruses, new DNA is synthesized from RNA, incorporated into the host DNA, and then used to produce RNA that synthesizes viral proteins (RNA→DNA→RNA→Peptide).

Reverse transcriptase inhibitors prevent integration and replication. Since only the viral DNA, and not the viral RNA, can integrate into the host genome and get replicated, these drugs can prevent further infection by blocking viral DNA synthesis.

Release and HIV protease inhibitors

Release is the third main stage of the HIV life cycle, when RNA and proteins that that make up the virus pack together and leave the cell to infect more cells. Viral RNA is translated into a polypeptide sequence, which is a long chain of proteins that are linked together. For these proteins to function properly, they must be cleaved (separated) by a viral protease so that each individual protein can be folded into a specific three-dimensional shape.

Drug treatments that target HIV protease can stop release from occurring. By blocking the ability of the viral protease to cleave the viral polypeptide into functional proteins, HIV protease inhibitors can prevent further infection.

Drug cocktails

Did you know? During the replication of DNA, guanine (G) is paired with cytosine (C) and adenine (A) with thymine (T). A combination of anti-HIV drugs (a drug cocktail) is always used for HIV treatment. HIV has a very high mutation rate because HIV reverse transcriptase has a high error rate during replication. Some of these mutations may result in a virus that is no longer susceptible to a particular drug. However, the chances that mutations would produce a virus that is resistant to all the drugs in the drug cocktail is very low.

* * *

Although there have been many advances in HIV treatment, the best strategy is to focus on prevention. And learning how the virus is transmitted is key to prevention. Given that HIV is spread mainly by having sex, it is particularly important to practice safe sex, which includes using condoms and limiting the number of sexual partners.

Learn more!

The HIV Life Cycle (2015)
AIDSinfo, US National Institutes of Health

Illustrated explanation of the HIV life cycle.

The epidemiology of HIV in Canada (2015)
Canadian AIDS Treatment Information Exchange

HIV Among Youth (2015)
US Centres for Disease Control and Prevention

HIV/AIDS Among Youth in Canada (2010)
Public Health Agency of Canada

Information on the extent and spread of HIV in Canada and the United States.

Advances in HIV treatment dramatically increase life expectancy (2013)
British Columbia Centre for Excellence in HIV/AIDS

Press release and infographic on how new treatments have extended the lives of people with HIV/AIDS.

Peptides from Second Extracellular Loop of C-?C Chemokine Receptor Type 5 (CCR5) Inhibit Diverse Strains of HIV-?1 (2012)
C. Dogo-Isonagie, Journal of Biological Chemistry 287

Mechanisms of inhibition of HIV replication by nonnucleoside reverse transcriptase inhibitors (2009)
N. Sluis-Cremera & Gilda Tachedjianb, Virus Research 134

Synthesis and SAR studies of potent HIV protease inhibitors containing novel dimethylphenoxyl acetates as P2 ligands (2003)
X. Chen et al., Bioorganic & Medicinal Chemistry Letters 13
Link to abstract. Subscription required to view full text.

Scientific articles on drug treatments for HIV.

leila khelghatybana

I recently completed a bachelors in cell and molecular biology and soon will start my masters studies in pharmacology.


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