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HIV-AIDS : One of the Biggest Global Threats of this Century
#1
One Day in the Doctor’s Clinic:  

Muhammad Ali is a poor truck driver. He has to travel months in truck, spending sleepless nights away from his family. But for last few weeks he cannot go to his work. He is suffering from flu and some other symptoms like sore on throat, rash, muscle and joint aches and pains. In spite of taking proper medications as per the doctor, no improvement occurred. Finally the doctor advised Ali to have a test, a test of HIV-AIDS and this is the day when he is supposed to have the confidential test report.

Doctor : "…Mr. Ali, as per the test reports, I am sorry to say , you are HIV positive….

Ali : (Breaks into tears) …doctor please recheck the reports…

Doctor: Sorry . I am helpless, all the test reports confirm you are HIV+ .

Ali : Doctor, AIDS doesn't have any medicine right? If my family and friends come to know about this, they will not even talk to me, they will leave me. I have heard AIDS spreads by shaking hand also, how can I live such a cursed life, doctor? Better you give me poison ! (with breaking voice and tears)

Doctor: Wait my dear, don’t be hopeless. You are not alone. There are millions of people in the world like you and I have told you are HIV+, but never told you are having AIDS. Yes, it doesn't have proper medicine to cure completely, but it can be controlled. You are lucky that you have got to know about this at very early stage. Now if you take the drug properly, you ‘ll have a normal life span, and one more thing, it is not an infectious disease, so if your friends shake hands with you, take lunch there is no way of transmission until you involve in a physical relationship or your blood gets in contact with the other…"

HIV & AIDS :  

Yes, Ali is not alone. There are around 37 million HIV+ around the world. But a person with HIV+ is not affected with AIDS? It is true indeed. HIV stands for Human Immunodeficiency Virus which is a retrovirus. Among different HIV, HIV-1 is the strain that affects the Human (Homo sapiens) . It breaks the immune system that actually protects a person from different diseases.  Suppose a country say India has its own defence mechanism to protect its people. Now if someway the border security force are killed and all the army base camps are destroyed by any external forces, all the terrorist groups and other neighbouring countries those want to damage India, will be happy to attack. Same way when HIV breaks down the immune system by destroying the CD4+ lymphocyte cells, all the microorganisms that healthy individuals can harbour with no illness, will cause serious disease in such impaired immunity. A simple fever may also be fatal. This is called AIDS i.e. Acquired Immunodeficiency Syndrome, a syndrome where the body becomes immunodeficient to protect a person. That means when HIV infection is at the very beginning, if one can control the virus population, he can still protect himself from developing AIDS.

So HIV is the cause of the resulting disease AIDS. In 2014 1.2 million people died of AIDS. But the difference with other viral disease with HIV is that once a person gets affected with HIV-1, he will carry it until the last day of his life. The only way to control this is to take regular Anti-Retroviral Therapy (ART) as prescribed by the doctor. AIDS is the extreme stage of HIV-1 infection when the body is no longer capable of defending the opportunistic diseases. The normal CD4+ T cell in a healthy person varies from 500 cells to 1600 cells per mm3 of blood. But when this number falls below 200 cells/mm3 one is supposed to develop AIDS.
 

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[Table-1: Created by Author, SOURCE: CDC guidelines for AIDS diagnosis, 1993 revision. Note: All categories coloured in Red is indicator of AIDS ]


Origin of HIV :
By using gene sequence evidences and other Phylogenetic analysis scientists have concluded that the present version of HIV (Human Immunodeficiency Virus-1) is a mutated form of SIV ( Simian Immunodeficiency Virus) which is found in the chimpanzee of Western Africa. It is thought that when ancient Africans hunted these chimpanzees the SIV entered to human body by direct contact of blood. With time it mutated itself in the human body and got spread through out the world.

Molecular Mechanism of HIV-1 Infection in Human :
Before going into the molecular mechanism of HIV-1 infection let us have a look on the HIV-1 genome organization. Many information about the life cycle of HIV-1 have been obtained by the in vitro studies of HIV-1 infected mammalian cells. HIV-1 is a retrovirus meaning it is having RNA as its genetic material. In this ribonucleotide sequence, there are 9 genes namely
gag :The gene product of gag are p17, p24, p9, p7 . These proteins are responsible for making the nucleocapsid of the offspring virus.
pol : The gene products are p64( having Reverse Transcriptase and RNase activity), p51(having reverse transcriptase activity), p10 (protease activity that cleaves the gag precursor) and p32 (with Integrase activity).
env : The resulting protein of this gene is gp 41 and gp 120. The gp 120 appears to play the most vital role to bind and interact with the CD4+ in T-cells while the gp 41 helps  in the fusion process.

Among other six genes tat, rev and nef encode for regulatory proteins, vif and vpu code for proteins essential for virion maturation and the last one vpr encodes for a weak transcriptional activator.


[Image: 2hdxwuh.jpg]

[Fig-1 : A. HIV-1 Structure. B. The HIV-1 gene organization. Created by Author. Source: Kuby Immunology 6th ed.]


Now let us consider the steps of HIV-1 infection in Human:


1) In the immune system both the T helper cell subpopulation and the macrophages play major role in defending the invading microorganisms. In case of HIV-1 , the transmembrane protein gp-120 on the surface of the virus can only interact with the CD4+ of the T helper cell as well as the monocytes. But, this interaction can’t turn to a successful attachment until a co-receptor helps. For T helper cell and macrophage it is CXCR4 and CCR5 respectively.
2) After the successful attachment the fusogenic domain of gp 41 and the G-protein coupled co-receptor (CXCR4 or CCR5) on the target cell enables the fusion of the plasma membrane with the virus capsid. Then the viral genome along with the enzyme machinery enter the cell keeping the coat outside.
3) After getting into the cell the reverse transcriptase makes RNA-cDNA hybrid from the information of ssRNA template. Next the original ssRNA template is degraded by ribonuclease and 2nd DNA strand is made to form dsDNA.
4) Then the viral ds DNA is translocated to the host cell nucleus and integrated into the genome by the integrase enzyme forming a Provirus stage.
5) The viral transcription factors now stimulate the host cell transcription and make ssRNA followed by the translation to make necessary proteins.
6) Next the ssRNA assembles with the proteins including gp 41 and gp 120 and buds out forming viral coat. Finally they release bursting the host cell.

This way the main two warrior of the immune system starts dying and the whole body becomes susceptible to opportunistic infections leading to AIDS.



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[Fig-2 Life Cycle of HIV Source:graphs.net]


The Symptoms :  

From the day of exposure to HIV-1 the symptoms differ in various patients with time. In many patients no usual symptoms appear and HIV remains undetected for several years until it ultimately develops to AIDS. That is why HIV can be only confirmed by testing an individual. There are mainly three phases of developing AIDS.

1) Acute Stage:These are the symptoms appearing due to the natural response of the body to the infection within the 3-4 weeks of exposure and often referred to Acute Retroviral Syndrome. The symptoms include
Flu with fever
Rash
Sore on the throat
Headache
Pain in the Muscle and the joints
2) Chronic Phase: After the acute phase which continues from few weeks to months, in the Chronic phase as the body tries to defend the HIV and able to do so to some extent mostly no or mild symptoms occurs. This lasts for about 10years. This is the stage where if the Anti Retroviral Therapy (ART) is taken a person can live his normal life span without developing AIDS.
3) AIDS : If no ART is taken HIV-1 keeps replicating and increasing their population by destroying the body’s natural defence system throughout the chronic phase. When they become successful in doing so in around 9-10years, the opportunistic diseases starts attacking, and actual symptoms of AIDS appears. Some of the symptoms are given below:
Rapid loss of weight
High fever with night sweats
Extreme tiredness
Swelling of the lymph glands in the armpits, groin, or neck
Diarrhea mostly lasts for few 1-2 weeks
mouth or genitals sores
Pneumonia
neurologic disorders like depression and memory loss.

Some very common opportunistic diseases at this stage are :
i) Candidiasis (caused by Candida albicans) : Sores in the mouth (thrush) appears.
ii) Vulvovaginal yeast infection that does not respond to treatment.
iii) Coccidioidomycosis (caused by a fungus called Coccidioides immitis): High fever.
iv) Cryptococcosis (caused by Cryptococcus neoformans) : This fungus enters through the lungs and cause pneumonia.
v) Tuberculosis (caused by Mycobacterium tuberculosis).


The Modes of Transmission of HIV-1:

There are many misconceptions among people about the transmission of HIV-1 from the patients to normal individual. It needs direct contact with at least one of the body fluids such as Blood, Semen, rectal fluids, pre-seminal fluids, vaginal fluids or breast milk.
Here is the list of possible modes of transmission:


[Image: e1cc6b015818ac10755caf4e1cc45af7.jpg]

[Fig-3: The Modes of HIV Transmission: Source: Aids.gov]

A) Most Common Route:
Sexual relationship between a HIV+ individual with an unaffected person is the most common way of HIV as reported till date. Among different sexual behaviour it is found that Anal sex is much more risker than the vaginal sex. In US most of the reported cases of HIV+ are the homosexual men.
• Also having multiple sex partner having high risk of transmitting HIV.


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[Fig-4: Different modes of HIV Transmission in US as per CDC 2010 data. Created by Author. Source: Source: Centers for Disease Control and Prevention. "HIV Infections Attributed to Male-to-Male Sexual Contact — Metropolitan Statistical Areas, United States and Puerto Rico, 2010" MMWR 61 (47): 962-966.]

Here is a well documented video that will explain different modes of HIV transmission including some preventive measures that will be discussed later in this article.




B) Possible other routes:  
• An infected mother can transmit HIV to her child during her pregnancy.
• By using syringe/needle that is already used by any HIV+ individual.
• At the time of blood transfusion or organ-transplantation.
• Any direct contact with the blood of the patient.

C) Impossible ways: Here is the misconceptions people have about the transmission of HIV. Genuinely speaking HIV is a virus and it cannot sustain outside the host cell environment. Even in semen it can hardly be viable 30sec outside the body. So, the following can never cause HIV-AIDS:
Air or Water
Mosquito bites or any kind of insects.
Shaking hands or hugging a HIV+ individual
Sharing Lunch-dinner in the same plate, this transmits LOVE not HIV.


How Do I  Know, if  I am Having HIV? Simple, Get Tested :

As already told before no symptom is enough to ensure the presence of HIV in an individual because from the acute phase to the AIDS symptoms vary significantly, sometimes it can disappear for years. So, the only way is to get diagnosed.  The most common way to test HIV is to detect the anti-HIV antibody present in the serum of the patients after months of the infection has occurred. When the body starts to make anti HIV antibody, the person is said to be Seroconverted or seropositive for HIV-1. The following graph shows the serologic profile of a patient over time.


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[Fig-5: Serologic profile of HIV infection showing three stages in the infection process. Source: Kuby Immunology , 6th Ed. ]

There are separate modes of diagnosing HIV infection. Some of those are discussed below.

1) Antibody screening test (Immunoassay): Most common test for antibody detection is ELISA (Enzyme Linked Immunosorbant Assay). It is having a sensitivity of 0.0001-0.01 microgram of antibody/ml of sample. The procedure of detecting HIV is shown in the image below.

[Image: 14ah2pt.jpg]

[Fig-6:  HIV Detection by ELISA Essay , SOURCE: http://tube.medchrome.com/2011/11/elisa-...-detection]

Though it is a very sensitive assay, sometimes it may give false negative results. As the body needs some time to develop antibody against the antigen from the day of infection. So, if the result comes negative in spite of having symptoms, the patient must have repeated test as the window period (the time between one gets exposed to HIV but no test can detect presence of HIV )vary from patient to patient.  As this is done as a part of screen test, some other tests (like Western Blot) needs to be done to ensure the infection once the ELISA test shows  positive result.


2) Western Blot Test : This is a test by which the different proteins of the HIV from the infected sample is separated by polyacraylamide gel elctrophoresis.  Generally blood sample is taken for study. When antibody for both the gag and env is detected by the ELISA or other antibody detecting assays, doctor confirms HIV infection after getting positive result in Western Blot.

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[Fig-7 Western Blot Pattern for HIV Test . Source: http://www.bio-rad.com ]


3) Viral Load test : Viral load is the amount of viral particle present per ml of blood in the HIV+ individual. This is detected any of the following procedure: RT-PCR , Branched chain DNA(bDNA) method or the nucleic acid sequence based amplification method.
This is generally done when someone is diagnosed  positive for HIV infection. This is because of the regular monitoring of viral load from the base value keeps the doctor on track how the patient is responding to the Anti Retroviral Therapy (ART).

4) CD4 Count: Along with Viral load test constant monitoring of CD4 count is also done. CD4 count id the number of CD4+ lymphocytes present per ml of blood. As the viral load and CD4 count is inversely proportional , i.e. if the no of virus particle increases definitely the no of CD4 lymphocytes will be destroyed and the immune system will get weaker with time. So both keeps the doctor on track.

5) Antibody Differentiation test: This test is done to ensure that the HIV infection is due to  HIV-1 or HIV-2 .  

6) Rapid Test : These test are very quick and reliable for screening. These tests use fluid samples like blood, oral or vaginal fluid  and gets the result within 20 mins. Presently a number of  Rapid HIV test kits are approved by FDA. Below is a very short video on Rapid HIV Testing.






7) Home-bases test:
Home Access HIV-1 Test System : This is an anonymous test. Here the patient will take the kit and after blood sampling send it to the FDA approved laboratory. The report can be obtained in the next 3-4 business days.
OraQuick In-Home HIV Test : This kit gives very quick result at home.



How to face this Global Threat?--The Prevention:

To prevent any disease, the first thing to be considered is to spread awareness about the disease. Based on the modes of transmission of HIV-1 , here are some few measures to prevent it.

1) Sexually transmission:
i) Take precautions like using condom (for both male and female).
ii) Don’t live a polygamy life and be honest to your partner.
iii) Live a sexually disciplined life.


2) Blood or other modes :
i) Screening blood samples. This must be done by the blood banks.
ii) Always use fresh needles or syringes.


In case of mother to child , testing should be done at the time of pregnancy. If the result is positive proper medication and advice should be taken from the doctor.

Above of all , if the report is positive for an individual , appropriate measures must be taken along with the full course of the Anti Retro Viral therapy as prescribed by the doctor.


Combat with HIV - The Anti Retroviral Therapy (ART)  :

A number of therapeutic agents have been developed to treat the HIV in the infected patient. All these anti retroviral drugs mainly target at different stages of HIV life cycle. Here is a short video featuring how HIV infects an individual and the machinery that can be blocked to reverse the effects in an infected person.






So, as shown in the video, the main targets of the Anti-Retroviral drug fall under four categories:

1) Blocking Reverse transcriptase action by Nucleoside and Non-nucleoside analogue: These are actually the nucleoside analogues that mimic the naturally occurring nucleosides. If these are incorporated into the growing chain of cDNA made by reverse transcriptase, there will be a chain termination and no functional cDNA will be made. Thereby stopping the lifecycle. Example of such FDA approved drugs are Zidovudine, or AZT (Azidothymidine).

2) Inhibitor of Protease : After the proteins are synthesized in the host cell , these need to be cleaved for making functional virus particle by the enzyme called Protease. These class of drugs inhibit the protease activity and thereby preventing the formation of new mature virion. Examples for such drugs are Nelfinavir (Viracept) , Indinavir (Crixivan) etc.

3) Inhibitor of Integrase : Scientists have developed drugs that can inhibit the integrase activity so that the viral dsDNA cannot integrate to the host cell genome. Currently FDA approved available drug for Integrase inhibitor is Isentress (generic name raltegravir) and Tivicay (generic name Dolutegravir). Researchers are still  working on in this topic.

4) Fusion Inhibitors-Blocking the attachment of HIV to the Host cell : Research is going on to develop therapeutic agents to target both gp 41 and CXCR 4 / CCR5 and stopping them from activating the G-coupled receptor signalling pathway. Currently FDA approved available drug for Fusion inhibitor is Fuzeon (generic name enfuvirtide, T-20).

Though the mode of action of these drugs are different, one single drug is not effective to treat HIV. For this reason often in ART, a combination of the nucleoside analogues and protease inhibitors are used. This is designated as HAART (Highly Active Anti-Retroviral Therapy). The main disadvantage of using all these drugs is most are not  HIV-1 specific. So, they once enter the host cell can equally affect the host cell machinery also and thus killing the host cell. Another point is that there are number of side effects seen in the patients taking ART.



A Look into the Current Research Scenario:

All the research going on different parts of the world focus on three aspects of combating HIV-1.

1)  Developing more effective Anti-Retroviral Therapy : This is the traditional approach followed by various scientist since HIV epidemic. Till date there are six lines of anti-retroviral drug developed in total. Introduction of HAART (highly active anti-retroviral therapy) significantly reduced the mortality rate of HIV patients. Scientists of the The Aaron Diamond AIDS Research Center, New York under The Rockefeller University are committed to find effective ways to target HIV and improve the efficiency of ART.  


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[Fig-8 : Changes in survival of people infected with HIV as more efficient ART is introduced with time. Source: Lohse et al (2007), "Survival of persons with and without HIV infection in Denmark, 1995-2005."]


2)Eradicating the HIV Reservoirs : It is true that HIV+ patients cannot be cured. Once a person gets affected he continues to carry it until his death. It doesn't matter how much efficient and effective ART you take. ART can help you only to lower down the viral load i.e. the number of virus in your body to an undetectable amount by blocking specific parts of the HIV life cycle. But it cannot make it to zero. Here the term comes called HIV Reservoirs. As we have seen the after getting into the host cell the cDNA made by the reverse transcriptase enzyme gets integrated to the host genome. Now if new virus particle manufacturing is disturbed by ART, still HIV is hidden with it’s genomic information within the infected blood cells. That is why after several years of taking ART course when one discontinues it, soon within few weeks the HIV symptoms reappear. So if the hidden HIV reservoirs can be eradicated fully only then a person can be cured. But this is not successful yet. The leading research on this aspect is being done by AIDS Research Alliance of America, Los Angeles, CA. They are trying to develop Prostratin , a strategy by which the HIV reservoirs can be eradicated. (A detailed update to this novel approach will be posted soon )


3) Developing HIV Vaccine : It is pretty sure that developing a vaccine is the only way to have a permanent cure of HIV. So far in human history most of the viral infectious diseases like small pox , polio are defeated by developing novel vaccine. But the problem for HIV is that vaccination can be done only when it is found that an individual is fully cured of HIV infection which is not reported yet. More over HIV is an infection not a disease. So the traditional vaccination phenomena don’t fit into this. But, ground breaking research is going on in various laboratories of the world. The International AIDS Vaccine Initiative, New York is one of the leading labs with high progress of developing the vaccine. (Why developing a HIV vaccine is such a challange? An update on this is coming soon )


4) Microbicides : Other aspects are developing some strategies like Microbicides which are gels, foams or creams that can be applied topically inside the vagina to prevent sexually transmission of HIV . National Institute of Allergy and Infectious Diseases under the National Institute of Health , US are doing some extraordinary research in this field.


A messege to the reader:

Dear reader , 1st December is coming soon. Like every year we all ‘ll observe this day by different events , campaign, slogan etc. to raise awareness and to support the HIV affected people. But what about the rest 364 days? In those days what most of us do is to maintain a safe distance to a person with HIV+. I don’t know if you have a prior knowledge about HIV-AIDS or not, but after reading this I hope you must have some clear ideas of it . Now I wish that you can help others to understand about this global threat and clear the myths-misconceptions about HIV-AIDS among the people around you. Every day about 5,600 people contract HIV which means approximately 230 every hour. There are many Muhammad Ali-s around us. We cannot cure them, we cannot make them HIV free. But we can make them smile for the rest of their life. It is obvious that we cannot help everyone but everyone can help someone. Spending time to give mental support to these helpless people is what we all can do. We can share our knowledge to make people aware about HIV transmission so that they have a disciplined sex life. All these will not make you a HIV+ but definitely make you a good human being. Spread Love, spread Happiness not HIV  Smile



For More information and Current research You can visit:

1) The American Foundation for AIDS Research, New York (http://www.amfar.org/)
2) CDC - Centers for Disease Control and Prevention, (http://www.cdc.gov/hiv/)
3) Aids.gov (https://www.aids.gov/hiv-aids-basics/)
4) U.S Food and Drug Administration (http://www.fda.gov )
5) National institute of allergy and infectious diseases (http://www.niaid.nih.gov/topics/hivaids/...fault.aspx)
6) The International AIDS Vaccine Initiative, New York (https://www.iavi.org)
7) Aids Info (https://aidsinfo.nih.gov/clinical-trials)

#2
Thumbs Up 
The fact that we should be more compassionate towards those suffering from HIV/AIDS has been dealt with the right amount of importance here. Overall, quite an engaging and interactive article!
#3
In Search of an HIV-AIDS free World : Update-I

Today, HIV-AIDS free world is just a dream. But, the scientists believe in transforming dreams into reality. As everyone knows that once a person gets affected he carries the HIV through out his life. The use of continuous HAART (Highly Active Antiretroviral Therapy)which is the latest standard therapy against HIV till date, can only control the number of virus particle in the body. It is possible that after taking HAART for few years, the viral load becomes undetectable in the blood. But that doesn’t mean the removal of HIV entirely from the system. A gap in taking HAART of 1-2 weeks can lead to increase the numbers significantly as shown in the graph below:

[Image: x1lymb.jpg]
[Fig-1 :  HIV Reservoir Persists During HAART , SOURCE: Davey Smith, MD, MAS, of UC San Diego AntiViral Research Center, slide "The Lastest on HIV Cure” http://www.slideshare.net/ucsdavrc/aids-...80114smith]

The reason is at the time of primary infection there are two possibilities:
1) Some of the CD4+ cells affected by HIV will face apoptotic death.
2) Some of the cells will enter a quiescent state leading to the formation of CD4+ memory cell where the genomic information of the HIV will be hidden as the Provirus state.

In the second case the latent HIV is unaffected by natural HAART because this affects only when the proteins are translated from the genomic information not the gene itself. Thus the latent HIV is kept hidden from the immune system also. In absence of HAART the viral genes are transcribed followed by translation producing mature viral particle and thereby expressing HIV-AIDS again. So, it is pretty sure that if these latent reservoirs are removed completely a fully cured HIV free body system can be achieved.

[Image: s2w4d0.jpg]
[Fig-2 The HIV latent reservoir.   a) Normal mechanism of T cell proliferation and formation of Memory cell; b) Formation of HIV reservoir (CD4+ lymphocytes) which is sometime reactivated by the secondary interaction with the antigen. SOURCE: Mayte Coiras, María Rosa López-Huertas, Mayte Pérez-Olmeda & José Alcamí, “Understanding HIV-1 latency provides clues for the eradication of long-term reservoirs”, Nature Reviews Microbiology 7, 798-812 (November 2009) | doi:10.1038/nrmicro2223]

One strategy is proposed by the leading scientists of AIDS Research Alliance of America, Los Angeles, CA. The target is to stimulate and activate the latent HIV Provirus genes and unmask them infront of the HAART. Once the CD4+ cells containing the viral genes express the viral proteins HAAT can easily target those and eradicate them from the system. This way if all the HIV reservoirs are stimulated and treated while taking HAART very soon the viral load will become zero to make the body HIV free.

The researchers of  AIDS Research Alliance have isolated a chemical compound called Prostatin which can act as an potential transcription factor to initiate the transcription of the viral gene. Prostratin is a member of a distinct subclass of protein kinase C (PKC) activators. By activating the  PKC pathway it initiates a series of  events that result in assembling the other necessary transcription factors that finally “turn on” viral gene expression. This compound is already patented by the institute (Methods of Administering prostratin and Structural Analogs Thereof, US Application No.: 12/937,364, European Patent Application No. 09730430.7).

[Image: 2cwne6b.jpg]
[Fig-3: The action of Prostratin, SOURCE:aidsresearch.org]

Also the right to produce Prostratin synthetically is granted to the institute by the Stanford University. The researchers have already progressed a lot to develop Prostratin into a potential drug. Once they become successful in doing so in different trial processes and get approved by the FDA , the world will get the first ever weapon to combat with HIV with the hope to defeat it completely.
The day is not far away when the dream of having a world without a single HIV-AIDS patient will be a reality !

To know more about the progress of developing Prostratin Visit : http://aidsresearch.org/cure-research/our-progress
#4
(10-14-2015, 11:27 PM)APARAJITA AICH Wrote: The fact that we should be more compassionate towards those suffering from HIV/AIDS has been dealt with the right amount of importance here. Overall, quite an engaging and interactive article!

Thank you so much Aparajita for your appreciation. Yes, we all have to fight together with the hope that one day we 'll be successful in bringing an end to this global threat. Smile
  




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