REVIEW ON PATHOPHYSIOLOGY and TREATMENT of HIV AIDS

More than 30 years have passed since the first case of HIV was reported. Till date only one case has been reported to have been cured from HIV. The drug combinatorial approach such as antiretroviral therapy (ART) brought a huge change in the life of HIV patients. The newer combinations are in the development process to combat HIV infection. 1st December 2016 is World AIDS day and, the present article provides information about some updated HIV treatments.
According to WHO, there are 36.7 million peoples living with HIV worldwide. About 1.1 million people died in 2015 because of AIDS. This scenario is more common in developing countries. AIDS is a final step of HIV infection. It is called silent killer because the HIV can remain dormant for many years and cause damage to immune system.
HIV-1 infection is predominantly a global pandemic. Antiretroviral therapy has revolutionized the lives of people living with HIV. In many countries, the life expectancy for someone living with the virus is now almost the same as someone who isn’t infected. But antiretroviral therapy is not a cure. Hence, HIV research continues to search for a cure.

 The major difficulties for a cure:

The biggest hurdle for anti-HIV drugs and vaccines is that the HIV frequently mutates which lead to resistance to most drugs. It is estimated that in a person the virus has billions of copies that too with frequent mutations. This is one primary reason for the development of drugs like zidovudine for inhibition of reverse transcriptase to deal with the mutations. Most of the vaccines targetting other infections are simply attenuated but for an HIV vaccine, attenuation cannot be an option due to possible reactivation. Less medical experience about subunits of HIV to develop subunit HIV vaccine also presents as a hurdle. Lack of ideal small models to study HIV infection brings about more limitations.

HIV is a retrovirus that integrates its own genome into the host genome and develops a high hiding ability from immune surveillance.

An interesting clinical case which cured HIV:

To date, there has been just one case of a cure for HIV. About 1 percent of Caucasians carry a gene mutation that triggers immunity to HIV. This gene is chemokine receptor type 5 (CCR5) which is useful for virus entry into CD4 cells. Because the gene is missing the virus can’t enter into CD4 cells. In a clinical case, a patient was diagnosed with HIV and unexpectedly developed myeloid leukemia. The patient’s doctor decided to go for stem cell transplantation and the donor picked by them was resistant to HIV as described above. This has eventually cured the HIV infection of that patient. However, this treatment cannot be applied at large scale as stem cell transplantation is risky and used even as the last option in leukemia patients.

Current treatment options:

Antiretroviral therapy (ART) brought a huge change in the life of HIV patients.

Non-nucleoside reverse transcriptase inhibitors (NNRTIs): The drugs such as efavirenz, etravirine, nevirapine, rilpivirine etc, inhibit the reverse transcriptase enzyme.

Nucleoside reverse transcriptase inhibitors (NRTIs): A combinatorial approach of abacavir, zidovudine as well as lamivudine can be effectively used to treat HIV infection.

Protease inhibitors (PIs): These drugs prevent the maturation of HIV virus by blocking its protease enzyme. Examples include amprenavir, atazanavir, indinavir, and nelfinavir.

Fusion inhibitor: It blocks the HIV from entering in the host CD4. Enfuvirtide is an approved fusion inhibitor drug.

Integrase strand transfer inhibitors (INSTIs): Integrase is an enzyme that helps the virus to integrate its genome into the host genome (DNA). Blocking this enzyme would prevent infection. Dolutegravir and elvitegravir are two examples of integrase inhibitors.

Tenofovir disoproxil fumarate (DF): Tenofovir DF is highly effective and generally safe and well-tolerated, but can cause kidney and bone problems for a few patients. Recently, its new form Tenofovir alafenamide (AF) requires low doses that minimize the risk of side effects.

Treatment plan under investigation:

Gene therapy: Gene therapy is directed to either make a cell resistant to HIV or to remove it from the cell. The initial target of gene therapy was CCR5. This same gene is missing in some rare individuals who are naturally resistant to HIV. Nowadays, use of restriction enzymes to target virus is underway. However, this approach of restriction enzyme is little difficult as the virus mutates readily and change the genetic code to which restriction enzyme can’t respond.

Boosting immune response: Immune checkpoint blockers are the drugs currently under clinical trials stage to boost immune response by reactivating the exhausted T cells. Another drug class called toll-like receptor agonist is also useful to boost immunity.

Future prospective:

A successful strategy should consider two points:

Reduce the persistent virus load after ART and boosting immune response.

Early diagnosis: It has been clinically suggested that early diagnosis is important because the antiretroviral therapy could significantly reduce the infected cells when given within days to weeks of infection.

Latency reversing agents: These are small molecules to help find where the HIV-1 is hiding in the cells. For example, 5-hydroxynaphthalene-1,4-dione (5HN) could activate the expression of HIV-1 proteins in latently infected cells and eliminate virus-expressing cells through immune- or virus-mediated cell death.

Next generation HIV therapies:

A new target for these drugs in future would be an HIV protein called Nef protein that destroys CD4 immune cells. Two things have changed fundamentally in HIV treatment. One is the nature of HIV treatment and other is the way people acquire knowledge. Finding a cure for HIV is yet a big scientific task, but it is within the realm of possibility and it will hopefully play an important role in seeing an end to HIV.