HIV virus particle

Side Chapter: Forms of HIV immunity/resistance

An interview on innate immunity to HIV

Abstract - This interview actually concurs the concept of innate immunity to HIV. The interviewee, Jay Levy from the University of California talks about a particular aspect of the cellular immune response known as CD8 cell antiviral factor which he believes play an important role in successfully suppress the viral load of HIV thereby limiting its progress. He also discuss the possibility that drug manufacturing companies could perhaps develop a vaccine that could induce similar effects on infected HIV-positive patients.

Lacking receptors that allow entrance of HIV virus

Abstract -- This articles shows that the innate immunity that some people have may be due to a genetic defect that result in the absence of  CCR5 receptor, the receptor that HIV take advantage of to gain entrance into a host cell. Interestingly, individuals who inherited a pair of the defected genes display apparent immunity to HIV infection. While individuals who inherited only one of the defected gene are not completely immune to HIV infection, they display greater resistance to the progression of the virus. 

Effective immune response that actively suppress viral load

Abstract -- This article attributed the ability to keep the virus load in check to the ability of the immune system killer T cells to recognize infected cells. Through a series of experiments, researchers have found that the underlying ability of these HIV controllers (people who are able to naturally suppress the viral load) may have to do with the unique protein sequence of the killer T cell receptors. The researcher also discuss about the possibility of developing a vaccine that could induce the production of these effective killer T cells.

Chapter II: How to kill HIV (HAART)

As promised, now that you have a greater understanding about the mechanism of HIV replication, now its time to explore some ways to counteract it or simply put kill it. Enjoy. ^^


Classes of drugs used in HIV treatment (Highly Active Antiretroviral Therapy)

1.      Nucleoside Analogs (Competitive substrate inhibitor) [1]

AIDS (acquired immunodeficiency syndrome) is caused by infection with the retrovirus HIV (human immunodeficiency virus). A key step in the life cycle of this virus is synthesis of a DNA copy of the viral RNA genome, catalyzed by a reverse transcriptase. Reverse transcriptase is a major target of chemotherapy because it is not essential for normal cells.


AZT (3’-azido-2’,3’-dideoxythymine; Zidovudine) was the first drug approved for treatment of HIV infection. It is a nucleoside analog with an azido group on the sugar. It can be phosphorylated into triphosphate from, which competes with dTTP (deoxythymine triphosphate) for incorporation into the reverse transcript. Once incorporated, it terminates the growing chain of the transcript because the azido group on the 3’ carbon of the sugar is not a substrate for nucleotide addition. AZT is much less efficient at competing with the more accurate cellular DNA polymerases, providing a therapeutic window in which the effect is primarily upon viral replication. (Since the effects of faulty DNA synthesis by AZT affects the virus more efficiently than it does human cells) Nevertheless, side effects include toxicity to bone marrow, which contains rapidly dividing cells, and myopathy that might be related to toxicity to mitochondria, which contain their own DNA polymerase (pol delta). DDI (2’, 3’ dideoxyinosine; didanosine) and dideoxycytidine (zalcitabine) also function as chain terminators after incorporation of their phosphorylated derivatives by the HIV reverse transcriptase.

2.      CCR5 receptor antagonist (Competitive substrate inhibitor) [2]

These are the first antiretroviral drugs which do not target the virus directly. Instead, they bind to the CCR5 receptor on the surface of the T-Cell and block viral attachment to the cell. Most strains of HIV attach to T-Cells using the CCR5 receptor. If HIV cannot attach to the cell, it cannot gain entry to replicate. Currently, three pharmaceutical companies are trying to push through FDA approval with their
small molecule CCR5 antagonist however Maraviroc is the only FDA approved drug as of now.





Putative binding of Maraviroc to the CCR5 receptor



The strongest interaction is estimated to be between maraviroc and glutamic acid (Glu283) through a strong salt-bridge interaction. Types of interaction with CCR5:
* II – T-shaped π-π stacking
* III – parallel displaced interaction
* V – hydrophobic interaction
* VI – limited interaction
* VII – salt-bridge interaction

3.    Reverse transcriptase inhibitor (Non-competitive inhibitors) [3]

Non-nucleoside reverse transcriptase inhibitors inhibit reverse transcriptase by binding to an allosteric site of the enzyme. (Thereby changing its shape and loss of enzymatic activity) Examples of these inhibitors are Efavirenz and Nevirapine.

             4.  Protease inhibitor (Non-competitive inhibitor}

Protease inhibitors (PIs) target viral assembly by inhibiting the activity of protease, an enzyme used by HIV to cleave nascent proteins for the final assembly of new virions. (Thereby resulting in immature HIV that is non-infectious)


       5.  Integrase inhibitor (Non-competitive inhibitor)
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, and raltegravir became the first to receive FDA approval in October 2007.

Reverse transcriptase do not carry out proofreading, thus their error rate is much higher than that of cellular DNA polymerases. This high error rate complicates the treatment of AIDS, because the population of viruses carried by any one patient contains many mutants. Some of these mutants are likely to be resistant to any given therapeutic agent. Thus, many drugs initially reduce the viral load, but later become ineffective due to the selective growth of the viruses in which the drug target is mutated to an insensitive form. Combination therapy, with multiple drugs that target different viral proteins, is an attempt to circumvent this problem.

How reverse transcriptase inhibitor works? (Animation)

http://www.hhmi.org/biointeractive/media/reverse_trans-lg.mov

How protease inhibitor works? (Animation)

http://www.hhmi.org/biointeractive/media/protease_inhibitor-lg.mov

References

http://en.wikipedia.org/wiki/Management_of_HIV/AIDS#Mega-HAART

[1] Glitz, D.(2006). Textbook of Biochemistry With Clinical Correlations Sixth Edition. Canada: Wiley-Liss.

[2] http://en.wikipedia.org/wiki/CCR5_receptor_antagonist#Mechanism_of_action

[3] http://en.wikipedia.org/wiki/Reverse_transcriptase_inhibitor

Chapter I: The Inner Workings of HIV

As far as the phrasing goes: Know your enemy and know your enemy well in order to win the day. It's a  little cliche but a touche ^^

In order to fully fathom the premise of HIV treatment or possibly cure, we must first be able to understand how this little midget works

Entry (This virus do know how to make an entrance^^): [1]

HIV infection is specific to certain human immune cells (helper T-cell) due to the presence of the protein CD4 (exclusive to helper T cells) which acts as a receptor that allow the virus to enter the cell; other than the CD4 receptor, a secondary receptor CCR5* (Chemokine Co-receptor) is also needed. After the virus attaches itself to these cell-surface receptors, it then fuses the viral membrane and the cell membrane and inject the viral particles into the cell while leaving its membrane protein behind.

Reverse Transcription and Integration

After the virus make its way into the cell, its matrix and capsid protein break down to release the viral genetic material. Then the enzyme, reverse transcriptase* that the virus brings along with it starts acting on the viral mRNA to transcribe a complementary DNA or cDNA. Now, another enzyme that the virus brought along, integrase* would bring the viral DNA into the cellular nucleus and integrate that piece of viral DNA into the human DNA, which dawns upon the start of a life-long infection as the virus take advantage of the cellular machinery to create more copies of itself and infect neighboring cells. Once integrated, the HIV DNA is known as provirus.

Transcription and Translation

HIV provirus may lie dormant within a cell for a long time. But when the cell becomes activated, it treats HIV genes in much the same way as human genes. First it converts them into messenger RNA (using human enzymes). Then the messenger RNA is transported outside the nucleus, and is used as a blueprint for producing new HIV proteins and enzymes.

[2]Interesting tidbits: While HIV only has 9 genes, it’s able to take advantage of mRNA slippage and a change in reading frame to generate different protein from the same message (Programmed frameshifting in biosynthesis of HIV protein). A single mRNA, designated gag-pol, encodes for two polyproteins that overlap by about 200 nucleotides and are in different reading frames. The gag polyprotein is translated from the initiation codon to an in-frame termination codon near the gag-pol junction.; gag polyprotein is then cleaved to generate several structural proteins of the virus. However about 5% of the time a one-nucleotide frameshift occurs within the overlapping segment of the mRNA and the termination codon is bypassed because it is no longer in the reading frame. A gag-pol fusion polyprotein is produced; proteolytic cleavage of the pol polyprotein produces the viral reverse transcriptase and other proteins needed in virus replication.

Assembly, Budding and Maturation

Among the strands of messenger RNA produced by the cell are complete copies of HIV genetic material. These gather together with newly made HIV proteins and enzymes to form new viral particles. The HIV particles are then released or 'bud' from the cell. The enzyme protease* plays a vital role at this stage of the HIV life cycle by chopping up long strands of protein into smaller pieces, which are used to construct mature viral cores. 

The newly matured HIV particles are ready to infect another cell and begin the replication process all over again. In this way the virus quickly spreads through the human body. And once a person is infected, they can pass HIV on to others in their bodily fluids.

If you are too lazy to read the whole process, here's an olive branch ^^:

http://www.hhmi.org/biointeractive/media/hiv_life_cycle-lg.mov

References:

[1] http://www.avert.org/hiv-virus.htm

[2] Glitz, D.(2006). Textbook of Biochemistry With Clinical Correlations Sixth Edition. Canada: Wiley-Liss.

http://www.niaid.nih.gov/topics/hivaids/understanding/biology/Pages/structure.aspx
http://en.wikipedia.org/wiki/HIV

Preface: Introduction to blog

This blog would be dedicated to NP Medical Biochemistry project, and we would be working on Blood-borne disease: HIV infection. Hope you enjoy^^


What is HIV? [1]

HIV or the Human Immunodeficiency Virus targets vital cells (helper T-cells, specifically CD4+ T-cells, macrophages and dendritic cells) in the human immune system thereby compromising one's ability to fight off infection. While someone may be HIV-positive (infected with HIV), the signs and syntomns of the infection may not be obvious or it may not even present any syntomns of unwell; which in the words of a virologist - HIV is a very good (elusive) virus or rather it presents an interesting set of problems. While there are therapies and drugs (High Active Antiviral Therapy HAART) that can specifically target the proliferating virus, a lot of times it just ends in empty hope; as that small window of being "cured" of the virus is but a brief respite, or a guise for the virus latency as it awaits safely within the host for another chance to start propagating. So while being infected may not affect a person in one or two day's time, it sure as hell would do a lot of damage as the AIDS becomes fully-blown, as the immune system give way to your daily interaction with a cocktail of diseases. (Perfect condition in which opportunistic infections and cancer thrives)




Signs & Syntomns of HIV infection [2]

As the HIV come out of it latency and it can start infecting the healthy cells that carry the protein CD4 (e.g macrophage , dendritic cells and CD4+ T cells). As the CD4+ T cells population dwindles due to HIV infection, the body's capability to recognize pathogens and target them also starts to fail; which enables these opportunistic pathogens that would normally elicit an immune response from the helper T-cell to bypass the screening process completely. This then increase the likelihood for opportunistic infections:

Opportunistic Infections: Brain

Cryptoccoccal Menigitis — This is a yeast-like fungus infection that usually involves the brain and lungs, although it can affect almost any organ. The fungus that causes this condition is found in soil throughout the world. It is most common in soil contaminated by bird droppings. This disease most often occurs when a person's CD4+ T cell count falls below 100 cells per cubic millimeter of blood.

HIV-related Encephalopathy — Encephalopathy is a term for diseases that alter brain function or structure, leading to problems with cognitive function, or mental processes, and memory. In people with HIV and AIDS, encephalopathy is usually caused by an infectious agent, such as a bacteria, virus or prion.

Encephalopathy most often occurs when a person's CD4+T cell count falls below 50 cells per cubic millimeter of blood. Toxoplasma-seropositive patients who have a CD4+T cell count of less than 100 cells per cubic millimeter of blood should be treated with prophylaxis to prevent developing encephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) — Progressive multifocal leukoencephalopathy is a rare disorder of the nervous system caused by a common human polyomavirus, JC virus. It leads to the destruction of the myelin sheath that covers nerve cells. The myelin sheath is the fatty covering that acts as an insulator on nerve fibers in the brain. Symptoms include mental deterioration, vision loss, speech disturbances, inability to coordinate movements, paralysis and ultimately coma. In rare cases, seizures may occur.

This disease can occur when the CD4+T cell count falls below 200 cells per cubic millimeter of blood.

Toxoplasmosis — This condition occurs when a parasite infects the brain. Symptoms include confusion or delusional behavior, severe headaches, fever, seizures and coma. It can affect the eye, causing eye pain and reduced vision.

Toxoplasmosis most likely occurs when the CD4+ T cell count falls below 100 cells per cubic millimeter of blood. Preventative treatment — usually with trimethoprim-sulfamethoxazole, also called Septra and Bactrim — may be administered when the CD4+ T cell count falls below 100 cells per cubic millimeter of blood.

Opportunistic Infections: Eyes

Cytomegalovirus (CMV) — Although this virus can affect the entire body, it commonly affects the eye's retina, causing blurry vision and in severe cases, blindness. Other common symptoms include chronic diarrhea and nerve problems. It is most likely to occur when a person’s CD4+ T cell count falls below 100 cells per cubic millimeter of blood.

Opportunistic Infections: Gastrointestinal Tract

Cryptosporidiosis — This is a parasite that can cause chronic diarrhea. Other symptoms include stomach cramps, nausea, fatigue, weight loss, appetite loss, vomiting and dehydration.

This infection is difficult to treat and there is no definitive effective treatment. Symptom control and treatment of HIV are necessary.

Cytomegalovirus — Although this virus can affect the entire body, it commonly occurs in the stomach, causing fever, diarrhea and stomach pain. It most likely occurs when the CD4+ T cell count falls below 50 cells per cubic millimeter of blood.

Mycobacterium Avium Complex — This is a bacterial infection that can cause persistent fever, night sweats, fatigue, weight loss, anemia, abdominal pain, dizziness, diarrhea and weakness. The bacteria that cause this infection is found in water, dust, soil and bird droppings.

This disease most likely occurs when the CD4+T cell count falls below 50 cells per cubic millimeter of blood. Preventive treatment, usually with azithromycin, is administered when CD4+ T cells are less than 50 cells per cubic millimeter of blood.

Opportunistic Infections: Genitals

Candidiasis — Candidiasis is an infection caused by the candida fungi. Also known as a yeast infection, it's the most common HIV-related fungus infection. It can affect the entire body, but most commonly occurs in the mouth, called thrush, or vagina. An overgrowth of yeast in the vagina can cause irritation, itching, burning and thick white discharge.

Herpes Simplex — This virus causes genital herpes, which are painful blisters in the genital area, or cold sores. Severe conditions are more common in the advanced stage of AIDS.

Human Papilloma Virus (HPV) — This condition is considered the most common sexually transmitted disease (STD) in the United States. It can cause warts on the anus, cervix, esophagus, penis, urethra, vagina and vulva. Studies have shown that certain types of HPV can contribute to the development of cervical and anal cancer. Individuals with HIV and AIDS are at increased risk for developing precancerous and cancerous lesions.

Opportunistic Infections: Liver

Liver Disease — Liver disease is one of the leading causes of death among AIDS patients, especially liver disease caused by the hepatitis B and hepatitis C virus. Many drugs used in the treatment of HIV and AIDS can cause liver disease or hepatitis. It is important that patients infected with hepatitis receive treatment and follow-up care.

Opportunistic Infections: Lungs

Coccidiomycosis — This infection is caused by inhaling an infective fungus called Coccidioides immitis, found mainly in contaminated soil in the southwestern United States, Mexico, Central America and parts of South America. The lungs are most commonly affected by this infection. In severe cases, it can involve the kidneys, lymph system, brain and spleen. Symptoms include cough, weight loss and fatigue. Meningitis is a common complication when left untreated.

Histoplasmosis — This infection almost always involves the lungs, although other organs may be affected. The fungus that causes this condition is found in southern parts of the United States and South America. It is usually found in soil contaminated with bird droppings and must be inhaled to cause infection.

Signs and symptoms include high fever; weight loss; respiratory complaints; an enlarged liver, spleen, or lymph nodes; depressed production of white cells, red blood cells and platelets from the bone marrow; and life-threatening, unstable, low blood pressure.

Pneumocystis Carinii — This condition occurs when a fungus infects the lungs. Symptoms may include fever, cough, difficulty breathing, weight loss, night sweats and fatigue.

It is most likely to occur when the CD4+ T cell count falls below 200 cells per cubic millimeter of blood. Preventative treatment may be administered when the CD4+ T cell count falls below 200 cells per cubic millimeter of blood. Treatment is usually trimethoprim-sulfamethoxazole, also called Septra or Bactrim, dapsone or atovoquone.

Recurrent Pneumonia — People with AIDS are at risk for recurrent bacterial pneumonia. Bacteria can infect the lungs, which may lead to problems ranging from a mild cough to severe pneumonia. Recurrent pneumonia is most likely to occur when the CD4+ T cell count falls below 200 cells per cubic millimeter of blood.

Tuberculosis (TB) — This is a serious, and often deadly, bacterial infection that primarily infects the lungs. TB is transmitted when a person with active TB coughs or sneezes, releasing microscopic particles into the air. If inhaled, these particles may transmit the condition.

Once infected by TB, most people remain healthy and develop only latent infection. People with latent infection are neither sick nor infectious. However, they do have the potential to become sick and infectious with active TB. It can occur at any CD4+ T cell level but especially when the CD4+ T cell count falls below 350 cells per cubic millimeter of blood.

Opportunistic Infections: Lymphatic System

Non-Hodgkin's Lymphoma — Non-Hodgkin's lymphoma is a disease in which tumors develop from white blood cells in the lymphatic system. It is another common disease associated with AIDS.

Opportunistic Infections: Mouth and Throat

Candidiasis — This is the most common HIV-related fungus infection. It can affect the entire body, but most commonly occurs in the mouth (thrush) or vagina. An overgrowth of yeast causes white patches on gums, tongue or lining of the mouth, pain, difficulty in swallowing and loss of appetite. Candida in the esophagus, trachea, bronchi or lungs is AIDS defining.

Opportunistic Infections: Skin

Herpes Simplex — This virus causes cold sores or genital herpes, which are painful blisters in the genital area. Chronic herpes simplex virus (HSV) lesions and severe mucocutaneous HSV disease are common in the advanced stages of AIDS.

Kaposi's Sarcoma — This is the most common AIDS-related cancer. It causes reddish-purple lesions that usually appear on the skin. They also can appear on the lymph nodes, mouth, gastrointestinal tract and lungs.

Shingles — Shingles are caused by a reactivation of the chicken pox virus. It may cause a painful rash or blisters that follow the path of nerves.

References
[1] http://en.wikipedia.org/wiki/HIV
[2] http://www.ucsfhealth.org/conditions/aids/signs_and_symptoms.html