Antiretroviral Treatment And The Hiv Lifecycle
Antiretroviral treatment for HIV combines several different types of drugs, each of which targets a different stage in the HIV lifecycle. This means that the replication of HIV is stopped on multiple fronts, making it very effective.
If taken correctly, it keeps the immune system healthy, prevents the symptoms and illnesses associated with AIDS from developing, and means that people can enjoy long and healthy lives.
If someone doesnt take their treatment correctly or consistently , the level of HIV in their blood may increase and the drugs may no longer work. This is known as developing drug resistance.
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Its a life-changing ridenot a racethrough some of Californias most beautiful countryside. Co-produced by San Francisco AIDS Foundation and the Los Angeles LGBT Center, AIDS/LifeCycle advances these agencies shared interest in reducing new HIV infections and improving the quality of life for people living with HIV/AIDS.
Viral Entry Into The Host Cell
As mentioned above under adsorption, the binding of a portion or domain of the HIV surface glycoprotein gp120 to a CD4 molecule on the host cell induces a change in shape that brings the chemokine receptor binding domains of the gp120 into proximity with the host cell chemokine receptor. This, in turn, brings about a conformational change that exposes a previously buried portion of the transmembrane glycoprotein gp41 enabling the viral envelope to fuse with the host cell membrane and Figure \). After fusion of the viral envelope with the host cell cytoplasmic membrane, the genome-containing protein core of the virus enters the host cell’s cytoplasm.
Animation: Penetration of HIV into Host Cell. The binding of a portion or domain of the HIV surface glycoprotein gp120 to a CD4 molecule on the host cell induces a change in shape that brings the chemokine receptor binding domains of the gp120 into proximity with the host cell chemokine receptor. This, in turn, brings about a conformational change that exposes a previously buried portion of the transmembrane glycoprotein gp41 enabling the viral envelope to fuse with the host cell membrane. After fusion of the viral envelope with the host cell cytoplasmic membrane, the genome-containing protein core of the virus enters the host cell’s cytoplasm.
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World Aids Day : Know About These 7 Stages Of Hiv Aids Infection
HIV Aids has different stages in which it infects your body. Here are some important stages of cycle of HIV you must know
HIV is a severe infection which is spread through various reasons. This is a transmissible virus which infects other people which there are some type of sexual or blood contact. Acquired immunodeficiency syndrome is a chronic problem which can potentially be life threatening at times. It affects your immune system and minimizes ability of your body to fight with infections and diseases. This is a sexually transmitted disease which can be categorized into various stages. Most people are unaware of these stages of HIV hence today we will try to inform you about them.
The Hiv Lifecycle In Detail
Like other living things, viruses need to be able to reproduce.
When viruses reproduce it is called replication. HIV uses CD4 immune cells to replicate. And each infected CD4 cell produces hundreds of new copies of new HIV particles.
The process is called the HIV lifecycle.Each replication cycle only lasts 1 to 2 days. It has several stages and different HIV drugs are active at different stages. HIV drugs are called inhibitors because they inhibit or stop parts of the cycle.
An important concept about ART, is that HIV drugs only work on CD4 cells in your body that are awake and actively producing HIV.
However, most CD4 cells in your immune system are sleeping or resting. The resting cells, even if they contain HIV, are not affected by ART.
Reaching HIV in resting cells is a main aim in HIV cure research.
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Budding Stage Of Hiv Life Cycle
After moving to the surface of the CD4 membrane, the HIV releases another enzyme called Protease that helps to cleave or break up the long chains of HIV proteins into short chains of proteins. These short chains of HIV proteins then combine to form the Mature HIV virus that is infectious and can then infect another new CD4 cell. By this repeated replication and infection, it reduces the CD4 cells count in the body and the immunity of the HIV patient goes down. Protease Inhibitors are the HIV Drugs that block this stage.
These are the 7 stages of HIV Replication Cycle and their associated classes of drugs used for blocking the steps in HIV Replication cycle .
The 7 Stages Of The Hiv Life Cycle Explained
#1 BindingThis is the very first stage of the HIV Lifecycle. The HIV virus attacks the CD4 cell and attaches Itself to the cell on its surface. It does this by first attaching to the CD4 cells receptor than the CCR5 or the CXCR4 coreceptor.
#2 FusionThe second stage of the HIV life cycle is called fusion and this is done after the virus has effectively attached itself to the CD4 cell. The entire HIV viral envelope will then fuse with the cell which allows it to gain entry into it.
#3 Reverse TranscriptaseThe third stage happens once the HIV virus has entered the CD4 cell. This allows the virus to release an HIV Enzyme or reverse transcriptase enabling it to convert the viruss genetic makeup. It converts its HIV RNA to HIV DNA. This conversion is what allows the HIV Virus to enter the cells nucleus to integrate with it.
#4 IntegrationWhen the HIV virus has successfully entered the CD4 cells nucleus it releases another HIV enzyme known as integrase. This is the enzyme the virus uses to integrate its own DNA into the infected CD4 cells DNA. This is the fourth step in the HIV virus life cycle.
#5 ReplicationThe fifth stage of the HIV life cycle is when the virus starts to form HIV proteins in long chains. `These are the protein chains that the HIV virus uses to replicate itself and spread to other CD4 cells in the body.
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Viral Latency And Protein Synthesis
After successful integration of the viral DNA, the host cell is now latently infected with HIV. This viral DNA is referred to as provirus. The HIV provirus now awaits activation. When the immune cell becomes activated, this latent provirus awakens and instructs the cellular machinery to produce the necessary components of HIV, like plastic pieces of a model airplane. From the viral DNA, two strands of RNA are constructed and transported out of the nucleus. One strand is translated into subunits of HIV such as protease, reverse transcriptase, integrase, and structural proteins. The other strand becomes the genetic material for the new viruses. Compounds that inhibit or alter viral RNA have been identified as potential antiviral agents.
The Structure Of The Human Immunodeficiency Virus
To view further electron micrographs of HIV, see the AIDS Pathology Tutorial at the University of Utah.
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The Timeline Of Hiv Infection
Treatments can now slow HIV from progressing to AIDS. However, treatment requires prompt testing and care after exposure to the virus. Despite improvements in treatment regimens, access to care remains a big problem. Even with the advent of multi-drug therapy, evidence reports that 680,000 people died from AIDS-related illness in 2020 alone.
When a person acquires HIV and does not receive treatment, the infection progresses through :
Reverse Transcription Stage Of Hiv Replication
For a HIV virus to replicate, it must change from RNA to DNA for HIV to effect this change, it uses a protein called Reverse Transcriptase. This enzyme then changes the HIV RNA to HIV DNA. Once the HIV DNA is produced, it can then enter the Nucleus of the CD4 cell now called the nucleus where the genetic materials are stored to enable reproduction and transfer of genes for animals to give birth to their kind). This stage is blocked by two classes of HIV drugs: Nucleoside Reverse Transcriptase Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors.
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Attachment Or Adsorption To The Host Cell
Initially, HIV uses a cellular protein called cyclophilin that is a component of its envelope to bind a low affinity host cell receptor called heparin. This first interaction enables the virus to initially make contact with the host cell. In order to infect a human cell, however, an envelope glycoprotein on the surface of HIV called gp120 must adsorbs to both a CD4 molecule and then a chemokine receptor found on the surface of only certain types of certain human cells.
Human cells possessing CD4 molecules include:
- T4-helper lymphocytes
- monocytes
- macrophages
- dendritic cells
Animation: Adsorption of HIV to a T4-Helper Lymphocyte. The HIV envelope gp120 must attach to both a CD4 molecule and a chemokine receptor on the surface of such cells as macrophages and T4-helper lymphocytes in order to enter the cell. The gp120 first binds to a CD4 molecule on the plasma membrane of the host cell. The interaction between the gp120 and the CD4 molecule on the host cell induces a change in shape that brings the chemokine receptor binding domains of the gp120 into proximity with the host cell chemokine receptor
- Scanning electron micrograph showing HIV infecting a T4-lymphocyte courtesy of CDC.
YouTube animation illustrating adsorption and penetration of HIV.
HIV infecting microglia cells in the brain appear to bind to a CD4 molecule and a chemokine receptor called CCR3 found on these macrophage-like cells.
Reverse Transcription Stage Antivirals
Nucleoside reverse transcriptase inhibitors
NRTIs block HIV from using the reverse transcriptase enzyme to replicate. Reverse transcriptase allows the virus to convert its RNA to DNA in the reverse transcription stage of its life cycle. The drug prevents the virus from copying its RNA into DNA accurately.
Non-nucleoside reverse transcriptase inhibitors
NNRTIs disable a key protein that HIV uses to replicate. They work in a similar way to NRTIs by stopping the virus from replicating itself.
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Stage : Chronic Infection
Some people may also refer to this stage as asymptomatic or latent HIV. During this time, the virus is still replicating through its life cycle, but doing so more slowly. People can live in this stage for years without any symptoms, not knowing that they have HIV.
This phase usually lasts a decade or more. However, people on HAART therapy may remain in this latent stage for longer. It is possible to pass HIV on to others if a person is not receiving or correctly taking this medication. Thankfully, the medication can reduce a persons viral load and the risk of transmission down to undetectable levels.
What The Life Cycle Means For Hiv Medication
HIV medications disrupt the virus by targeting its life cycle at different stages. The problem is that HIV replicates very quickly. This gives it more opportunities to make mistakes in its own genetic code, and these mutations can make it resistant to a single medication over time.
Because of this, a doctor may use several classes of medications to halt the virus at different phases of its life cycle. This is the philosophy behind
first drug to be approved for HIV treatment was zidovudine, or AZT, in 1987. AZT targets the virus in its third stage of writing itself from RNA into DNA. By inhibiting reverse transcriptase, AZT prevents viral replication and protects normal cells. It falls under the category of nucleoside reverse transcriptase inhibitors .
Another class of HIV medications are protease inhibitors. These prevent immature HIV from maturing and replicating in its final life cycle stage. Examples of protease inhibitors include saquinavir and darunavir .
Integrase strand transfer inhibitors block the enzyme integrase, preventing the virus from writing itself into host DNA. Dolutegravir , cabotegravir , and raltegravir are all examples of INSTIs.
Some medications use two classes of drug together, called combination medications. These can make it easier for people to manage their regimen, because people with HIV can be on several treatments that require them to take medications at specific times of the day. It is important that people with HIV take their medications
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Cleavage And Viral Assembly
Once the various viral subunits have been produced and processed, they must be separated for the final assembly into new virus. This separation, or cleavage, is accomplished by the viral protease enzyme.
Drugs called protease inhibitors — such as Kaletra, Crixivan, and Viracept — bind to the protease enzyme and prevent it from separating, or cleaving, the subunits.
If cleavage is successfully completed, the HIV subunits combine to make up the content of the new virons. In the next step of the viral life cycle, the structural subunits of HIV mesh with the cell’s membrane and begin to deform a section of the membrane. This allows the nucleocapsid to take shape and viral RNA is wound tightly to fit inside the nucleocapsid. Researchers are looking at drugs called zinc finger inhibitors, which interfere with the packaging of the viral RNA into the nucleocapsid.
Ensure Healthy Lives And Promote Well
Since the creation of the Millennium Development Goals there have been historic achievements in reducing child mortality, improving maternal health and tackling HIV/AIDS, tuberculosis, malaria and other diseases. In 15 years, the number of people newly infected by HIV each year has dropped from 3.1 million to 2 million and over 6.2 million lives were saved from malaria. Since 1990, maternal mortality fell by 45 percent, and worldwide there has been an over 50 percent decline in preventable child deaths globally.
Despite this incredible progress, AIDS is the leading cause of death among adolescents in sub-Saharan Africa, and 22 million people living with HIV are not accessing life-saving antiretroviral therapy. New HIV infections continue to rise in some locations and in populations that are typically excluded or marginalised.
Chronic and catastrophic disease remains one of the main factors that push households from poverty into deprivation. Non-communicable diseases impose a large burden on human health worldwide. Currently, 63% of all deaths worldwide stem from NCDs â chiefly cardiovascular diseases, cancers, chronic respiratory diseases and diabetes. The cumulative economic losses to low- and middle-income countries from the four diseases are estimated to surpass US$ 7 trillion by 2025. Additionally, there continues to be underinvestment in the social circumstances and environmental factors affecting health. The job on HIV and health is far from done.
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Stage : Acute Infection
After exposure to HIV, the virus is in its acute phase for 24 weeks. During this period HIV is infiltrating the body and invading the CD4 cells. Blood levels of the virus are high.
The body reacts to this assault with flu-like symptoms people may experience headache, fever, and a rash, or they may have no symptoms at all. During this phase, there is high risk of transmitting the virus to another person.
Replication Of Hiv Within The Host Cell
The vast majority of T4-lymphocytes, which are productively infected, immediately begin producing new viruses. In the case of the small percentage of infected, resting memory T4-lymphocytes, before replication can occur, the HIV provirus must become activated. This is accomplished by such means as antigenic stimulation of the infected T4-lymphocytes or their activation by factors such as cytokines, endotoxins, and superantigens.
Following activation of the provirus, molecules of mRNA are transcribed off of the proviral DNA strand by the enzyme RNA polymerase II. Once synthesized,HIV mRNA goes through the nuclear pores into the rough endoplasmic reticulum to the host cell’s ribosomes where it is translated into HIV structural proteins, enzymes, glycoproteins, and regulatory proteins).
A 9 kilobase mRNA is formed that is used for three viral functions:
a. Synthesis of Gag polyproteins . These polyproteins will eventually be cleaved by HIV proteases to become HIV matrix proteins , capsid proteins , and nucleocapsid proteins . See Figure \A and Figure \B.
b. Synthesis of Gag-Pol polyproteins . These polyproteins will eventually be cleaved by HIV proteases to become HIV matrix proteins , capsid proteins , proteinase molecules , reverse transcriptase molecules , and integrase molecules . See Figure \C and Figure \D.
c. During maturation, these RNA molecules also become the genomes of new HIV virions.
The 9kb mRNA can also be spliced to form a 4kb mRNA and a 2kb mRNA.
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Replication Stage Of Hiv Life Cycle
In the Nucleus of the CD4 cell, the HIV DNA combines with the CD4 DNA so that anytime the CD4 cell wants to produce, it uses the cells proteins to produce more HIV long chains Proteins thereby multiplying the HIV protein copies. This stage of HIV Life Cycle is called Replication and not Reproduction as in animals. There is currently no drug that blocks this stage.
What Is The Hiv Life Cycle
HIV attacks and destroys the CD4 cells of the immune system. CD4 cells are a type of white blood cell that play a major role in protecting the body from infection. HIV uses the machinery of the CD4 cells to multiply and spread throughout the body. This process, which is carried out in seven steps or stages, is called the HIV life cycle.
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