A Positive Hope Towards HIV

In past there have been many failed trials to find out the cure for HIV. Every failure teaches a new lesson and shows new direction.
Finding the way from failures, our scientists came up with some prevention and limiting its multiplication tricks.

1. Mutant host gene CCR5 resist HIV:

What is CCR5?

C-C chemokine receptor type 5 is also known as CCR5 or CD195. It is a protein present on the surface of white blood cells that is involved in the immune system which acts as a receptor for chemokines. Chemokines are a family of small cytokines, or signaling proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells, they are chemotactic cytokines.

The CCR5 gene that encodes the CCR5 protein in humans which is located on the short (p) arm at position 21 on chromosome 3. Certain populations have inherited the Delta 32 mutation, resulting in the genetic deletion of a portion of the CCR5 gene. Homozygous carriers of this mutation are resistant to M-tropic strains of HIV-1 infection.

How does it helps in HIV prevention?

CCR5 and/or CXCR4 are most commonly uses the chemokine receptors by HIV-1 as co-receptors to enter target immunological cells. These receptors are located on the surface of host immune cells, they provide a method of entry for the HIV-1 virus for infecting the cell. The HIV-1 envelope glycoprotein structure is essential in enabling the viral entry of HIV-1 into a target host cell. The envelope glycoprotein structure consists of two protein subunits cleaved from a Gp160 protein precursor encoded for by the HIV-1 env gene:

• the Gp120 external subunit and

• the Gp41 transmembrane subunit.

Note:Env is a viral gene that encodes the protein forming the viral envelope. The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane.

This envelope glycoprotein structure is arranged in spike-like structure which is located on the surface of the virion and consists of a trimer of Gp120-Gp41 hetero-dimers. The Gp120 envelope protein is a chemokine mimic. Though it lacks the unique structure of a chemokine, it is still capable of binding to the CCR5 and CXCR4 chemokine receptors.  During HIV-1 infection, the Gp120 envelope glycoprotein subunit binds to a CD4 glycoprotein and a HIV-1 co-receptor expressed on a target cell which forms a heterotrimeric complex. The formation of this complex stimulates the release of a fusogenic peptide which lead the viral membrane to fuse with the membrane of the target host cell. Because binding to CD4 alone can sometimes result in gp120 shedding. gp120 must next bind to co-receptor CCR5 in order for fusion to proceed. The tyrosine-sulfated amino terminus of CCR5 co-receptor is the "essential determinant" of binding to the gp120 glycoprotein. The co-receptor also recognizes the V1-V2 region of gp120 and the bridging sheet which is an antiparallel, 4-stranded β sheet that connects the inner and outer domains of gp120. The V1-V2 stem can influence co-receptor usage through its peptide composition as well as by the degree of N-linked glycosylation. Unlike V1-V2 however, the V3 loop is highly variable and hence is the most important determinant of co-receptor specificity. The normal ligands for this receptor, RANTES, MIP-1β, and MIP-1α, are able to suppress HIV-1 infection in vitro. In individuals infected with HIV, CCR5-using viruses are the predominant species isolated during the early stages of viral infection, suggesting that these viruses may have a selective advantage during transmission or the acute phase of disease. Moreover, at least half of all infected individuals harbor only CCR5-using viruses throughout the course of infection.

CCR5 is the primary co-receptor used by gp120 sequentially with CD4. This binding results in gp41 which is the other protein product of gp160 which is to be released from its metastable conformation and insert itself into the membrane of the host cell. Although it has not been confirmed, binding of gp120-CCR5 involves two crucial steps:

• The tyrosine-sulfated amino terminus of this co-receptor is an "essential determinant" of binding to gp12.

• Following the first step, there must be reciprocal action (synergy, intercommunication) between gp120 and the CCR5 transmembrane domains.

CCR5 is essential for the spread of the R5-strain of the HIV-1 virus. Knowledge of the mechanism by which this strain of HIV-1 mediates and spread infection has prompted research into the development of therapeutic interventions to block CCR5 function. A number of new experimental HIV drugs, called CCR5 receptor antagonists, have been designed to interfere with binding between the Gp120 envelope protein and the HIV co-receptor CCR5. These experimental drugs include PRO140 (CytoDyn), Vicriviroc (Phase III trials were cancelled in July 2010) (Schering Plough), Aplaviroc (GW-873140) (GlaxoSmithKline) and Maraviroc (UK-427857) (Pfizer).

Maraviroc was approved for use by the FDA in August 2007.  It is the only one thus far approved by the FDA for clinical use, hence becoming the first CCR5 inhibitor. A problem of this approach is that, CCR5 is the major co-receptor by which HIV infects cells but it is not the only such co-receptor by which HIV infects cells. It is possible that under selective pressure HIV will evolve to use another co-receptor. However, the examination of viral resistance to AD101 which is a molecular antagonist of CCR5, indicated that resistant viruses did not switch to another co-receptor (CXCR4), but persisted in using CCR5. They either bound to alternative domains of CCR5 or to the receptor at a higher affinity.

Note: Since there is still another co-receptor available, it is a probability that presence the CCR5 mutant gene does not make one immune to the virus. It would simply be more challenging for the individual to contract it.

And also the virus still has access to CD4. Unlike CCR5, which is not required (as evidenced by those living healthy lives even when lacking the gene as a result of the delta32 mutation), CD4 is critical in the body's immune defense system.  Even without the availability of either co-receptor (even CCR5), the virus can still invade cells if gp41 were to go through an alteration (including its cytoplasmic tail) that resulted in the independence of CD4 without the need of CCR5 and/or CXCR4 as a doorway.

2. The antiretroviral therapy(ART): 

Standard antiretroviral therapy (ART) consists of the combination of at least three antiretroviral (ARV) drugs which maximally suppress the HIV virus and stop the progression of disease. Huge reductions have been seen in rates of death and suffering when use is made of a potent ARV regimen, particularly in early stages of the disease.

Antiretroviral therapy was introduced in 1996 in response to the poor success rate among those taking only one HIV medication at a time.

The beginnings of three-drug antiretroviral treatment was a turning point in the history of HIV treatment. The new treatment design for HIV transformed what used to be a diagnosis with a very poor outlook into a manageable condition.

Antiretroviral therapy has the following positive effects on HIV:

• stops HIV from multiplying in the blood.
• reduces viral load, the number of HIV copies in the blood.
• increases the number of CD4 cells, which are immune cells that HIV targets, to improve immune system function.
• slows down and prevents the development of stage 3 HIV, or AIDS.
• prevents transmission via sex.

• reduces the severity of complications and increases survival rates.
• keeps virus counts low in the blood.

When prescribing antiretroviral therapy, healthcare providers typically use a regimen of three or more drugs for the best chances of lowering the amount of HIV in the body. According to the Centers for Disease Control and Prevention (CDC), antiretroviral therapy can reduce viral load to such an extent that it is undetectable. This means that a person can no longer transmit the virus to another person, even via condomless sex.

There are seven classes of HIV drug, including around 30 different medications:

•     non-nucleoside reverse transcriptase inhibitors (NNRTIs)
•     nucleoside reverse transcriptase inhibitors (NRTIs)
•     post-attachment inhibitors
•     protease inhibitors (PIs)
•     CCR5 antagonists
•     integrase strand transfer inhibitors (INSTIs)
•     fusion inhibitors

The antiretroviral therapy starting regimen for adults and adolescents with HIV is usually one of the following:

• dolutegravir (Tivicay) + tenofovir/emtricitabine (Truvada) 
• bictegravir/tenofovir alafenamide/emtricitabine (Biktarvy)
• raltegravir (Isentress) + tenofovir/emtricitabine (Truvada) 
• abacavir/dolutegravir/lamivudine (Triumeq), but not for those with a genetic sensitivity to abacavir

When HIV multiplies, many of the new copies have mutation, they are slightly different from the original virus. Some mutant viruses keep multiplying even when you are taking ARV drugs. When this happens, the virus can develop resistance to the drug and ART may stop working.
If only one or two ARV drugs are used, it is easy for the virus to develop resistance. For this reason, using just one or two  drugs is not recommended. But if two or three drugs are used, a successful mutant would have to “get around” all of the drugs at the same time. Using combination therapy means that it takes much longer for resistance to develop.
ARVs reduce the viral load, the amount of virus in your bloodstream, but are not a cure. A blood test measures the viral load. People with undetectable viral loads stay healthier longer. They are also less likely to transmit HIV infection to others.

Some people’s viral load is so low that it is “undetectable” by the viral load test. This does not mean that all the virus is gone, and it does not mean a person is cured of HIV infection.

Though we cant change the page, at least we can read the current page correctly, thanks to all the failed trials.  We may not have a cure but we definitely have prevention and suppressing drugs.