Hiv Life Cycle And Antiretroviral Drug Targets
Understanding the basic HIV life cycle is the foundation for understanding the mechanism of action of the different classes of antiretroviral medications. The following discussion will focus on key HIV enzymes and relevant steps in the HIV life cycle related to HIV antiretroviral therapy. The Howard Hughes Medical Institute has produced an excellent HIV Life Cycle video that summarizes the key steps in the HIV life cycle.
Blocking The Virus From Entering The Cell
The first steps of the HIV infection cycle, where HIV attaches to and enters the human cell, can be blocked with compounds known as entry or fusion inhibitors.
- CCR5 blockers, such as , as well as CXCR4 blockers, are examples of these ARV drugs. They work by blocking cell receptors, called CCR5 and CXCR4, respectively, and prevent HIV from attaching to the host cell, interrupting the HIV life cycle in its earliest stages.
- gp120 inhibitors, such as DS003, bind to the gp120 proteins HIV needs to attach to healthy cells. Like CCR5 and CXCR4 blockers, gp120 inhibitors prevent the virus from attaching to and entering healthy cells.
- gp41 inhibitors can also interfere with these first steps by blocking the viral gp41 protein and therefore the ability of HIV to fuse with human immune cells.
Recommendations For Initiation Of Antiretroviral Therapy
The Adult and Adolescent ARV Guidelines recommend initiation of antiretroviral therapy for all persons with HIV to reduce morbidity and mortality associated with HIV infection and to prevent HIV transmission to others . In addition, antiretroviral therapy should be started immediately, or as soon as possible, after the HIV diagnosis.
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What Are Drug Interactions
Your HIV medications can be affected by other medicines, including other prescription drugs you are taking and drugs you buy over the counter at a pharmacy. Even herbal therapies, nutritional supplements, and some things found in common foods can affect your HIV medicines.
When one drug affects how another drug behaves, this is called a drug-drug interaction. For example, some drugs become less effective or cause side effects when they are taken with certain other drugs.
When something in food affects how a drug behaves, it is called a drug-food interaction. For example, grapefruit juice, taken at the same time as certain drugs, can boost the amount of these drugs in your bloodstream to an undesirable level. Everyone taking HIV drugs needs to be very careful about these interactions. Luckily, many of these interactions are well known to your provider and can be managed.
Your provider can give you a list of drugs and foods to avoid, depending on what treatment you are taking. Ask for this information for each drug that you are taking.
Also, be sure that you tell your provider about every single medication, drug, supplement, and herb you are taking–whether you got them by prescription or not.
Initiation Of Antiretroviral Therapy
Antiretroviral drug treatment guidelines have changed over time. Before 1987, no antiretroviral drugs were available and treatment consisted of treating complications from opportunistic infections and malignancies. After antiretroviral medications were introduced, most clinicians agreed that HIV positive patients with low CD4 counts should be treated, but no consensus formed as to whether to treat patients with high CD4 counts.
In April 1995, Merck and the National Institute of Allergy and Infectious Diseases began recruiting patients for a trial examining the effects of a three drug combination of the protease inhibitor indinavir and two nucleoside analogs. illustrating the substantial benefit of combining 2 NRTIs with a new class of anti-retrovirals, protease inhibitors, namely indinavir. Later that year David Ho became an advocate of this hit hard, hit early approach with aggressive treatment with multiple antiretrovirals early in the course of the infection. Later reviews in the late 90s and early 2000s noted that this approach of hit hard, hit early ran significant risks of increasing side effects and development of multidrug resistance, and this approach was largely abandoned. The only consensus was on treating patients with advanced immunosuppression . Treatment with antiretrovirals was expensive at the time, ranging from $10,000 to $15,000 a year.
Treatment as prevention
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Drug Interactions For Azt
The following drugs interact or have the potential to interact with AZT. These lists are not exhaustive.
AZT should never be combined with d4T , as these drugs interfere with each other.
The following drugs can affect the bone marrow, decreasing the production of white and/or red blood cells. Using AZT with these or other drugs that affect the bone marrow can increase the risk of infections and/or anemia:
- valproic acid
AZT should be used cautiously with these drugs, or not at all.
For some people, but not all, methadone increases the blood level of AZT. Aspirin, codeine, morphine and a number of other drugs can also affect the metabolism of AZT, so use of these drugs should be discussed with your doctor.
The antibiotic clarithromycin can reduce the absorption of AZT. This can be avoided by taking the two medications at least two hours apart.
How Hiv Drugs Work
There are currently five categories of HIV antiviral drugs available that have FDA approval. These categories are:
nucleoside reverse transcriptase inhibitors
nucleotide reverse transcriptase inhibitors
non-nucleoside reverse transcriptase inhibitors
Fusion inhibitors work outside the CD4 cell by inhibiting HIV from joining, or fusing, with the cell. Nucleosides, nucleotides and non-nucleosides all work to stop HIV from infecting CD4 cells. Protease inhibitors stop infected cells from reproducing the virus.
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How Does Combination Therapy Work
HIV treatment prevents the virus from multiplying in the body.
It works like this: in order to replicate, HIV enters certain human cells and takes control of the cell. Instead of producing new human cells, the cell now creates new HIV viruses. Some drugs prevent the virus from entering the cell in the first place. Others prevent HIV from taking command of the cell. And still others prevent the cell from producing new viruses.
One drug alone is not enough, as the virus produces many different versions of itself in the replication process. Different drugs work against each of the variations of HIV.
But if you take several different drugs, they attack HIV more effectively. The drugs stop the virus with combined force. This method is called combination therapy.
When to start treatment with anti-HIV drugs depends largely on two blood test results. The “viral load” indicates how high the level of the virus is in the blood. The number of helper T cells makes it possible to estimate how badly the virus has already weakened the body’s immune system .
As long as there are no signs of illness, treatment is usually started when viral load is 50,000 to 100,000 , or when the number of helper T cells drops to less than 350 per microliter of blood .
Breaks in treatment
There may be times when HIV-positive people need or would like to stop taking anti-HIV drugs for a period of time for example, because they are traveling.
HIV specialist doctors
Hiv Protein Processing And Hiv Protease Inhibitors
The HIV protease enzyme is a 99-amino-acid dimer made up of two identical subunits . This enzyme has a key role in post-transcriptional processing of the Gag and Gag-Pol polyproteins. The HIV protease has three major conformational forms: open, semi-open, and closed . The protease enzyme has an active site near the center of the heterodimer and the active site includes two opposed aspartic acid residues. Movement from the open to closed causes the flap ends to overlap and functionally act as a molecular scissor.
Polyprotein Processing and Maturation
The HIV protease inhibitors are structurally complex molecules that bind to the active site of HIV protease and inhibit the protease enzyme activity . The HIV protease inhibitors disrupt the normal Gag and Gag-Pol polyprotein processing, causing arrest of the normal maturation process, which thereby prevents infection of new cells. The protease inhibitors do not have an impact on cells already infected with HIV .
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How Do Hiv Nrtis Work
Once the virus enters the CD4 cells or T cells of the immune system, it begins to replicate or make copies of itself. During viralreplication, the step where the RNA of the virus gets converted into DNA is known as reverse transcription. Reverse transcriptase is an HIV enzyme that helps the virus to convert its RNA into DNA.
NRTIs prevent the reverse transcriptase enzyme from accurately replicating its RNA into DNA.
What Should People Know About Taking Hiv Medicines
Taking HIV medicines keeps people with HIV healthy and prevents HIV transmission. Taking HIV medicines every day and exactly as prescribed also reduces the risk of drug resistance.
But sometimes HIV medicines can cause side effects. Most side effects from HIV medicines are manageable, but a few can be serious. Overall, the benefits of HIV medicines far outweigh the risk of side effects. In addition, newer HIV medicines cause fewer side effects than medicines used in the past. As HIV treatment continues to improve, people are less likely to have side effects from their HIV medicines.
HIV medicines can interact with other HIV medicines in an HIV regimen or with other medicines a person is taking. Health care providers carefully consider potential drug interactions before recommending an HIV regimen.
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Which Protease Inhibitor Will I Take
There are five approved protease inhibitors: ritonavir and nelfinavir are for use by adults and children, while indinavir and the two forms of saquinavir are approved for adults only. Invirase was approved in 1995, and Fortovase, a new, stronger form of saquinavir was approved in 1997. The company that makes both drugs will continue to make Invirase available to people who already take that form of saquinavir through Spring 1998. After that, it will be available to them under a limited distribution program. A decision about which drug to take should be made with a doctor who knows your individual condition, and has medical knowledge of HIV disease. By finding out about the available treatment options, you can talk to your doctor about the risks and benefits of different drug combinations.
Hiv And Aids Medication
There is no cure for HIV and AIDS, but medicines can help. Many people with HIV live long and relatively healthy lives.
HIV damages your immune system by attacking blood cells that help fight infection.
Acquired Immune Deficiency Syndrome is the condition that develops if HIV is not treated.
The medications used to fight HIV are called antiretrovirals. They work to stop the virus multiplying. This helps to protect your immune system from damage caused by HIV.
The medications used to treat HIV and AIDS may be similar.
If your immune system has already been damaged, treatment can help stop further damage and even allow the immune system to partly repair itself.
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Tips For Staying On Your Treatment Plan
Before you start a treatment plan, you should:
- Get your health care provider to write everything down for you: names of the drugs, what they look like, how to take them , and how often to take them. This way, youll have something to look at in case you forget what youre supposed to do.
- With your providers help, develop a plan that works for you.
How Hiv Treatment Works
HIV treatment does not cure HIV, but it stops the virus from reproducing in your body. It can reduce the amount of virus in the blood to undetectable levels, meaning that you cannot pass on HIV.
Treatment with anti-HIV drugs is sometimes called combination therapy because people usually take three different drugs at the same time often combined into one tablet.
It’s also known as antiretroviral therapy , or highly active antiretroviral therapy – HAART for short.
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What Are The Types Of Hiv/aids Medicines
There are several different types of HIV/AIDS medicines. Some work by blocking or changing enzymes that HIV needs to make copies of itself. This prevents HIV from copying itself, which reduces the amount of HIV in the body. Several medicines do this:
- Nucleoside reverse transcriptase inhibitors block an enzyme called reverse transcriptase
- Non-nucleoside reverse transcriptase inhibitors bind to and later change reverse transcriptase
- Integrase inhibitors block an enzyme called integrase
- Protease inhibitors block an enzyme called protease
Some HIV/AIDS medicines interfere with HIV’s ability to infect CD4 immune system cells:
- Fusion inhibitors block HIV from entering the cells
- CCR5 antagonists and post-attachment inhibitors block different molecules on the CD4 cells. To infect a cell, HIV has to bind to two types of molecules on the cell’s surface. Blocking either of these molecules prevents HIV from entering the cells.
- Attachment inhibitors bind to a specific protein on the outer surface of HIV. This prevents HIV from entering the cell.
In some cases, people take more than one medicine:
- Pharmacokinetic enhancers boost the effectiveness of certain HIV/AIDS medicines. A pharmacokinetic enhancer slows the breakdown of the other medicine. This allows that medicine to stay in the body longer at a higher concentration.
- Multidrug combinations include a combination of two or more different HIV/AIDS medicines
Takeaways For Avoiding Drug Resistance
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How Do Protease Inhibitors Work
Protease inhibitors are antiviral drugs. They interrupt the way HIV uses a healthy cell to make more virus. When HIV enters a healthy cell, its only goal is to make more viruses to infect other healthy cells. It does this by making the cell produce certain proteins the virus can use to copy itself. Two of the proteins used by the virus are reverse transcriptase and protease. The goal of the protease inhibitor is to stop the protease from helping to assemble a new virus.
The diagram above shows the virus entering the cell , the cell making new proteins , the proteins forming a new virus and the cell releasing the new virus to infect other cells . It also shows some steps in the process that can be interrupted by protease inhibitors and other antiviral drugs that are taken along with protease inhibitors.
What Should People Living With Hiv Do If They Develop Drug Resistance For The First Time
If you develop drug resistance, Wohl advised taking the time to figure out if something went wrong, and to try to keep it from happening again.
Was adherence difficult? Did drug supplies run out? Addressing the underlying cause while moving on to second-line treatment is important to minimize the risk of failure of the new regimen, said Young.
Get help from your clinic and your support network, if possible. If missing doses was the issue, it can be difficult to change the things that made it hard to take meds every day. But you have to try, said Wohl.
The good news is that todays second-line antiretroviral treatments can be both very effective in suppressing resistant virus, and still be very well tolerated. Irrespective of what type of first-line treatment was used, second-line use of integrase inhibitors or boosted protease inhibitors can be successful, Young added.
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What Factors Are Considered When Choosing An Hiv Treatment Regimen
When choosing an HIV treatment regimen, people with HIV and their health care providers consider the following factors:
- Other diseases or conditions that the person with HIV may have, such as heart disease or pregnancy.
- Possible side effects of HIV medicines.
- Potential interactions between HIV medicines or between HIV medicines and other medicines the person with HIV is taking.
- Results of drug-resistance testing . Drug-resistance testing identifies which, if any, HIV medicines will not be effective against a persons HIV.
- Convenience of the treatment regimen. For example, a regimen that includes two or more HIV medicines combined in one pill is convenient to follow.
- Any issues that can make it difficult to follow an HIV treatment regimen. For example, a lack of health insurance or an inability to pay for HIV medicines can make it hard to take HIV medicines consistently every day.
The best HIV treatment regimen for a person depends on their individual needs.