HIV/AIDS

HIV

 What is HIV ?

HIV stands for human immunodeficiency virus. It is the virus that can lead to acquired immunodeficiency syndrome, or AIDS, if not treated. Unlike some other viruses, the human body can’t get rid of HIV completely, even with treatment. So once you get HIV, you have it for life.

HIV is a virus that attacks cells in the immune system, which is our body’s natural defence against illness. The virus destroys a type of white blood cell in the immune system called a T-helper cell, and makes copies of itself inside these cells. T-helper cells are also referred to as CD4 cells.

HIV attacks the body’s immune system, specifically the CD4 cells (T cells), which help the immune system fight off infections. Untreated, HIV reduces the number of CD4 cells (T cells) in the body, making the person more likely to get other infections or infection-related cancers. Over time, HIV can destroy so many of these cells that the body can’t fight off infections and disease. These opportunistic infections or cancers take advantage of a very weak immune system and signal that the person has AIDS, the last stage of HIV infection.

No effective cure currently exists, but with proper medical care, HIV can be controlled. The medicine used to treat HIV is called antiretroviral therapy or ART. If taken the right way, every day, this medicine can dramatically prolong the lives of many people infected with HIV, keep them healthy, and greatly lower their chance of infecting others.

Structure of HIV virus

1.    Shape and size

• HIV is a spherical virus of about 90 nm in diameter.
• Size; 90nm

1. Envelope:

• HIV is enveloped virus. The envelope is a lipid bilayer surrounding the viral matrix, which is derived from host cell membrane during budding.
• Below the envelope, there is an icosahedral shell called matrix (P17).

1. Core:

• The core consists of cylindrical capsid (P24) which surrounds the genome.

1. Genome:

• HIV is ss RNA virus. The genome consists of two identical copies of +SS RNA and protein which are linked at their 5’ end.
• Genome of HIV consists of 9 gene, 3 structural gene and 6 non-structural gene (regulatory gene).
• Structural gene (env,gag and pol), regulatory gene (tat,rev,nef,vif,vpr and vpu in HIV-I and vpx in HIV-2)

1. Enzymes:

• Reverse transcriptase (RNA dependent DNA polymerase)
• Protease
• Intrigase
• Ligase

1. Other properties:

• Oncogenic
• Mutation
• Species specific
• Family: Retroviridae
  
  
  HIV genome and proteins

• HIV has two identical copies of +SS RNA genome. The genome consists of 3 structural gene and 6 regulatory gene.
• Structural gene; env, gag and pol gene
• Regulatory gene; tat, rev, nef, vif, vpr and vpu in HIV-I and vpx in HIV-2)
  
  
  1. Structural gene:
  i. Gag gene:

• Gag gene encodes the precursor protein P55 which is cleaved by viral protease (P10) to form matrix protein (P17), Capsid protein (P24) and Nuncleocapsod protein (P7 & P9). Gag gene helps to form core of virus.
  ii. Pol gene:

• Pol gene encodes the precursor protein P100 which is cleaved to form Protease (P10), reverse transcriptase and endonuclease.
  iii. Env gene:

• Env gene encodes the precursor protein gp160 which is cleaved to form surface spike glycoprotein (gp120) and transmembrane protein (gp41).
• Genetic variety of HIV strain resides in env.
  
  
  2. Regulatory gene:
  i. Tat gene: ( transactivator of transcription)

• It encodes transactivator protein (P14) which promotes the transcription of viral genome.
  ii. Rev gene: (regulatory of expression of viral protein)

• It encodes Rev protein (P19) and promotes the expression of viral structural proteins
  iii. Nef gene: ( Negative expression factors)

• It encodes precursors protein P27
• It down regulates the expression of CD4 cells, macrophage and MHC-II.
  iv. Vif gene: (Virion infectivity factor)

• It encodes the precursor protein p23 and promotes the viral infectivity by suppression the inhibitory actions of host cell proteins.
  v. Vpr gene:

• It encodes the precursor protein P15.
• It promotes the transport of viral pre-initiation complex into nucleus of host cell.
  vi. Vpu gene in HIV-I / Vpx gene in HIV-II

• It encodes the precursor protein P16.
• It promotes maturity and releases of progeny virus from host cell.
• Replication cycle
  Stages of HIV Life Cycle or Steps of HIV Replication

1. Binding or Attachment stage
2. Fusion stage
3. Reverse transcription
4. Replication
5. Integration 
6. Assembly
7. Budding

Binding stage of HIV Life Cycle

In the binding or attachment stage of HIV Life cycle, the HIV virus attaches itself to the surface of CD4 cells by using its receptor known as gp120 (a glycoprotein) to attach to some receptors on the CD4 cells such as CCR5 receptors and CXCR4. The HIV virus only infects CD4 cells because these cells express the receptors that help the HIV virus to enter the cells. It is due to this infection that the HIV brings down the immune system of the body because the CD4 cells maintain the immunity of the body. This stage of HIV replication is inhibited by CCR5 drugs used for treatment of HIV infection.

Fusion stage of HIV Replication Cycle

After binding to the CD4 cell, the HIV virus then fuses its envelope (which serves as the covering of the virus) with the cell membrane of the CD4 cell. This enables the Virus to gain entry into the CD4 cell. This stage of HIV Replication is blocked by Fusion inhibitorswhich are drugs used for treatment of HIV infection.

Reverse transcription stage of HIV Replication

For a HIV virus to replicate, it must change from RNA (RiboNucleic Acid) to DNA (DeoxyriboNucleic Acid); for HIV to effect this change, it uses a protein (enzyme) 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 (remember that it fused with the CD4 membrane to enter the cytoplasm; in the cytoplasm is another compartment (or organelle) 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.

Integration stage of HIV Replication Cycle

Inside the CD4 nucleus, HIV then uses an enzyme known as Integrase to integrate (or insert) its vital DNA into the DNA of the CD4 cell. This stage is blocked using Integrase Inhibitors drugs.

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.

Assembly stage of HIV Life Cycle

Once the HIV long chains proteins are produced, they move out of the Nucleus to the surface of the CD4 membrane to assemble into immature noninfectious HIV.

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.

HIV to AIDS

This is the stage of HIV infection that occurs when your immune system is badly damaged and you become vulnerable to opportunistic infections. When the number of your CD4 cells falls below 200 cells per cubic millimeter of blood (200 cells/mm3), you are considered to have progressed to AIDS. (In someone with a healthy immune system, CD4 counts are between 500 and 1,600 cells/mm3.) You are also considered to have progressed to AIDS if you develop one or more opportunistic illnesses, regardless of your CD4 count.

Without treatment, people who progress to AIDS typically survive about 3 years. Once you have a dangerous opportunistic illness, life-expectancy without treatment falls to about 1 year. ART can be helpful for people who have AIDS when diagnosed and can be lifesaving. Treatment is likely to benefit people with HIV no matter when it is started, but people who start ART soon after they get HIV experience more benefits from treatment than do people who start treatment after they have developed AIDS.

People living with HIV may progress through these stages at different rates, depending on a variety of factors, including their genetic makeup, how healthy they were before they were infected, how much virus they were exposed to and its genetic characteristics, how soon after infection they are diagnosed and linked to care and treatment, whether they see their healthcare provider regularly and take their HIV medications as directed, and different health-related choices they make, such as decisions to eat a healthful diet, exercise, and not smoke.

Sign and symptoms

The symptoms of HIV at each stage can vary in type and severity from person-to-person and some people may not get any symptoms at all for many years. Without antiretroviral treatment, the virus replicates in the body and causes more and more damage to the immune system. This is why people need to start treatment as soon as possible after testing positive.

Stage 1: Acute primary infection

Around one to four weeks after getting HIV, some people will experience symptoms that can feel like flu. These may not last long (a week or two) and you may only get some of the flu symptoms – or none at all. Experiencing these symptoms alone is not a reliable way of diagnosing HIV.

You should always visit your healthcare professional if you’re worried about or think you’ve been at risk of getting HIV, even if you don’t feel unwell or have any of the following symptoms. They can then arrange for you to get tested.

Symptoms can include:

• fever (raised temperature)
• body rash
• sore throat
• swollen glands
• headache
• upset stomach
• joint aches and pains
• muscle pain.

These symptoms can happen because your body is reacting to the HIV virus. Cells that are infected with HIV are circulating throughout your blood system. Your immune system, in response, tries to attack the virus by producing HIV antibodies - this process is called seroconversion. Timing varies but once you have HIV it can take your body up to a few months to go through the seroconversion process.

It may be too early to get an accurate HIV test result at this point ,but the levels of virus in your blood system are high at this stage.

Because you may not know that you (or your partner) have HIV, condoms are the best way to protect yourself and your partner when having sex. Using a condom is especially important if you think you have been exposed to HIV.

Stage 2: The asymptomatic stage

Once a person has been through the acute primary infection stage and seroconversion process, they can often start to feel better. In fact, HIV may not cause any other symptoms for up to 10 or even 15 years (depending on age, background and general health). However, the virus will still be active, infecting new cells and making copies of itself. If left untreated, over time, this will cause severe damage to the immune system.

Stage 3: Symptomatic HIV infection

By the third stage of HIV infection a person’s immune system is severely damaged. At this point, they’re more likely to get serious infections, or bacterial and fungal diseases that the body would otherwise be able to fight off. Symptoms can include:

• weight loss
• chronic diarrhoea
• night sweats
• fever
• persistent cough
• mouth and skin problems
• regular infections
• serious illness or disease.
•  

• Treatment

• Antiretroviral Therapy
  
  
• HIV medications can help lower your viral load, fight infections, and improve your quality of life. But even if you take them, you can still give HIV to others. They're not a cure for HIV.
• The goals for these medicines are to:
• Control the growth of the virus
• Improve how well your immune system works
• Slow or stop symptoms
• Prevent transmission of HIV to others
• The FDA has approved more than two dozen antiretroviral drugs to treat HIV infection. They're often broken into six groups because they work in different ways. Doctors recommend taking a combination or "cocktail" of at least two of them. This is called antiretroviral therapy, or ART.
• Your doctor will let you know specifically how you should take your medications. You need to follow the directions exactly, and you shouldn't miss even one dose. If you miss doses, you could develop drug-resistant strains of HIV, and your medication may stop working.
  
  
• Classes of drugs
  
  
• Schematic description of the mechanism of the four classes of currently available antiretroviral drugs against HIV
• There are six classes of drugs, which are usually used in combination, to treat HIV infection. Antiretroviral (ARV) drugs are broadly classified by the phase of the retrovirus life-cycle that the drug inhibits. Typical combinations include 2 Nucleoside reverse transcriptase inhibitors (NRTI) as a "backbone" along with 1 Non-Nucleoside reverse transcriptase inhibitor (NNRTI), protease inhibitor (PI) or Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) as a "base."
• 
  
• Entry inhibitors
• Entry inhibitors (or fusion inhibitors) interfere with binding, fusion and entry of HIV-1 to the host cell by blocking one of several targets. Maraviroc and enfuvirtide are the two currently available agents in this class. Maraviroc works by targeting CCR5, a co-receptor located on human helper T-cells. Caution should be used when administering this drug however due to a possible shift in tropism which allows HIV to target an alternative co-receptor such as CXCR4. In rare cases, individuals may have a mutation in the CCR5 delta gene which results in a nonfunctional CCR5 co-receptor and in turn, a means of resistance or slow progression of the disease. However, as mentioned previously, this can be overcome if an HIV variant that targets CXCR4 becomes dominant. To prevent fusion of the virus with the host membrane, enfuvirtide can be used. Enfuvirtide is a peptide drug that must be injected and acts by interacting with the N-terminal heptad repeat of gp41 of HIV to form an inactive hetero six-helix bundle, therefore preventing infection of host cells.
  
  
• Nucleoside/nucleotide reverse transcriptase inhibitors
• Nucleoside reverse transcriptase inhibitors (NRTI) and nucleotide reverse transcriptase inhibitors (NtRTI) are nucleoside and nucleotide analogues which inhibit reverse transcription. HIV is an RNA virus and hence unable to become integrated into the DNA in the nucleus of the human cell; it must be "reverse" transcribed into DNA. Since the conversion of RNA to DNA is not done in the mammalian cell it is performed by a viral protein which makes it a selective target for inhibition. NRTIs are chain terminators such that once incorporated, work by preventing other nucleosides from also being incorporated into the DNA chain because of the absence of a 3' OH group. Both act as competitive substrate inhibitors. Examples of currently used NRTIs include zidovudine, abacavir, lamivudine, emtricitabine, and tenofovir.
• Non-nucleoside reverse transcriptase inhibitors
• Non-nucleoside reverse transcriptase inhibitors (NNRTI) inhibit reverse transcriptase by binding to an allosteric site of the enzyme; NNRTIs act as non-competitive inhibitors of reverse transcriptase. NNRTIs affect the handling of substrate (nucleotides) by reverse transcriptase by binding near the active site. NNRTIs can be further classified into 1st generation and 2nd generation NNRTIs. 1st generation NNRTIs include nevirapine and efavirenz. 2nd generation NNRTIs are etravirine and rilpivirine. HIV-2 is naturally resistant to NNRTIs.
  
  
• Integrase inhibitors
•  Integrase inhibitors (also known as integrase nuclear strand transfer inhibitors or INSTIs) inhibit the viral 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, and raltegravir became the first to receive FDA approval in October 2007. Raltegravir has two metal binding groups that compete for substrate with two Mg2+ ions at the metal binding site of integrase. As of early 2014, two other clinically approved integrase inhibitors are elvitegravir and dolutegravir.
  
  
• Protease inhibitors
• Protease inhibitors block the viral protease enzyme necessary to produce mature virions upon budding from the host membrane. Particularly, these drugs prevent the cleavage of gag and gag/pol precursor proteins. Virus particles produced in the presence of protease inhibitors are defective and mostly non-infectious. Examples of HIV protease inhibitors are lopinavir, indinavir, nelfinavir, amprenavir and ritonavir. Darunavir and atazanavir are currently recommended as first line therapy choices. Maturation inhibitors have a similar effect by binding to gag, but development of two experimental drugs in this class, bevirimat and vivecon, was halted in 2010.Resistance to some protease inhibitors is high. Second generation drugs have been developed that are effective against otherwise resistant HIV variants.
  
  
• Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
• NRTIs force the HIV virus to use faulty versions of building blocks so infected cells can't make more HIV.
• Abacavir, or ABC (Ziagen)
• Didanosine, or ddl (Videx)
• Emtricitabine, or FTC (Emtriva)  
• Lamivudine, or 3TC (Epivir)
• Stavudine, or d4T (Zerit)
• Tenofovir, or TDF (Viread), or TAF (Vemlidy)
• Zidovudine, or AZT or ZDV (Retrovir)
• Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
• These are also called "non-nukes." NNRTIs bind to a specific protein so the HIV virus can't make copies of itself, similar to jamming a zipper.
• Delavirdine, or DLV  (Rescriptor)
• Efavirenz, or EFV (Sustiva)
• Etravirine, or ETR (Intelence)
• Nevirapine, or NVP (Viramune)
• Rilpivirine, or RPV (Edurant)
• Protease Inhibitors (PIs)
• These drugs block a protein that infected cells need to put together new HIV virus particles.
• Amprenavir (Agenerase)
• Atazanavir, or ATV (Reyataz)
• Darunavir, or DRV (Prezista)
• Fosamprenavir, or FPV (Lexiva)
• Indinavir, or IDV (Crixivan)
• Lopinavir + ritonavir, or LPV/r (Kaletra)
• Nelfinavir, or NFV (Viracept)
• Ritonavir, or RTV (Norvir)
• Saquinavir, or SQV (Invirase, Fortovase)
• Tipranavir, or TPV (Aptivus)
• Fusion Inhibitors
• Unlike NRTIs, NNRTIs, and PIs -- which work on infected cells -- these drugs help block HIV from getting inside healthy cells in the first place.
• Enfuvirtide, or ENF or T-20 (Fuzeon)
• CCR5 Antagonist
• Maraviroc, or MVC (Selzentry), also stops HIV before it gets inside a healthy cell, but in a different way than fusion inhibitors. It blocks a specific kind of "hook" on the outside of certain cells so the virus can't plug in.
• Integrase Inhibitors
• These stop HIV from making copies of itself by blocking a key protein that allows the virus to put its DNA into the healthy cell's DNA. They're also called integrase strand transfer inhibitors (INSTIs).
• Bictegravir, or BIC (combined with other drugs as Biktarvy)
• Dolutegravir, or DTG (Tivicay)
• Elvitegravir, or EVG (Vitekta)
• Raltegravir, or RAL (Isentress)
• Monoclonal Antibody
• This is a new class of antiviral medication specifically for adults living with HIV who have tried multiple HIV medications and whose HIV has been resistant to current available therapies. Ibalizumab-uiyk (Trogarzo) blocks your body’s HIV infected cells from spreading the virus into those which are uninfected. It is administered by IV.
• Cobicistat (Tybost) is a drug that helps some drugs (atazanavir, darunavir, elvitegravir) work better, but it can increase the levels of other medicines you may be taking (always tell your doctor about these other medicines).
• Atazanavir + cobicistat, or ATV/c (Evotaz)
• Darunavir + cobicistat, or DRV/c (Prezcobix)
• Elvitegravir + TDF + FTC + cobicistat, or EVG/c/TDF/FTC (Stribild)
• Elvitegravir + TAF + FTC + cobicistat, or EVG/c/TAF/FTC  (Genvoya)
• Fixed-Dose Combinations
• Some drug manufacturers put together specific medicines into a single pill so they're easier to take, including:
• Abacavir + dolutegravir + lamivudine, or ABC/DTG/3TC (Triumeq)
• Abacavir + lamivudine, or ABC/3TC (Epzicom)
• Abacavir + lamivudine + zidovudine, or ABC/3TC/ZDV (Trizivir)
• Atazanavir + cobicistat, or ATV/c (Evotaz)
• Atazanavir + cobicistat, or ATV/c (Evotaz)
• Bictegravir +   emtricitabine + tenofovir alafenamide, or BIC/FTC/TAF (Biktarvy)
• Dolutegravir + rilpivirine, or DTG/RPV (Juluca)
• Durunavir + cobicistat, or DRV/c (Prezcobix)
• Efavirenz + emtricitabine + tenofovir, or EFV/FTC/TDF (Atripla)
• Elvitegravir + cobicistat + emtricitabine + tenofovir, or EVG/c/FTC/TAF  (Genvoya)
• Elvitegravir + cobicistat + emtricitabine + tenofovir, or EVG/COBI/FTC/TDF or ECF/TDF (Stribild)
• Emtricitabine + rilpivirine + tenofovir, or FTC/RPV/TAF (Odefsey)
• Emtricitabine + rilpivirine + tenofovir, or FTC/RPV/TDF (Complera)
• The following are some of the HIV medications available in the U.S.:
• abacavir (Ziagen)
• abacavir/lamivudine or 3TC (Epzicom)
• abacavir/dolutegravir/lamivudine or 3TC” (Triumeq)
• amprenavir (Agenerase)
• atazanavir (Reyataz)
• atazanavir/cobicistat (Evotaz)
• bictegravi/emtricitabine/ tenofoviralafenamide (Biktarvy)
• delavirdine (Rescriptor)
• didanosine or ddI (VidexEC)
• dolutegravir (Tivicay)
• dolutegravir/rilpivirine (Juluca)
• durunavir (Prezista)
• durunavir/cobicistat (Prezcobix)
• efavirenz (Sustiva)
• elvitegravir (Vitekta)
• elvitegravir/tenofovir disoproxil fumarate/emtricitabine/cobicistat (Stribild)
• elvitegravir/tenofovir alafenamide/emtricitabine/cobicistat (Genvoya)
• emtricitabine/tenofovir alafen (Truvada)
• enfuvirtide (Fuzeon)
• emtricitabine or FTC (Emtriva)
• etravirine (Intelence)
• fosamprenavir (Lexiva)
• ibalizumab-uiyk (Trogarzo)
• indinavir (Crixivan)
• lamivudine or 3TC (Epivir)
• lopinavir ritonavir (Kaletra)
• maraviroc (Selzentry)
• nelfinavir (Viracept)
• nevirapine (Viramune)
• raltegravir (Isentress)
• rilpivirine (Edurant)
• rilpivirine/ tenofovir disoproxil fumarate or TDF (Complera)
• rilpivirine/tenofovir alafenamide (“TAF”)/FTC (Odefsey)
• ritonavir (Norvir)
• saquinavir (Fortovase, Invirase)
• stavudine (Zerit)
• tenofovir alafenamide or TAF (Vemlidy)
• tenofovir alafenamide/FTC (Descovy)
• tenofovir disoproxil fumarate or TDF (Viread)
• tenofovir disoproxil fumarate/FTC (Truvada)
• tipranavir (Aptivus)
• zalcitabine or ddC (Hivid)
• zidovudine or AZT (Retrovir)
• zidovudine/3TC (Combivir)
• zidovudine/3TC/abacavir (Trizivir)