The Cure for HIV and AIDS

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HIV and AIDS are not any more strange words as these words have become common in our day-to-day life and are getting discussed by various media outlets including print as well as electronic media. We have seen an exponential growth of scientific knowledge about HIV/and AIDS in last 3 decades. However, medical and scientific communities are still struggling with the fact that "HIV infections can only be controlled and cannot be cured." This statement translates into the fact that if someone gets infected with HIV s/he has to remain infected throughout his/her life and finally has to die with full blown AIDS. HIV is one of the most well studied viruses and AIDS is one of the most studied diseases in modern time, still scientists are unable to crack the mystery to cure this disease. Various theories, therapies, and strategies are being tried to save humanity from HIV/AIDS, but it seem like that they failed, failed and failed!!! to cure HIV infections. It seems like all the money spent on researches went down the drains, as it is almost 30 years since HIV was discovered, but none of the HIV patients were cured or saved from this infection, so far. In recent past, it seems like the cloud of darkness about cure of HIV started seeing some light, as we see a possibility to cure HIV once and forever. Although, it is too early to be too optimistic, but there is nothing wrong to raise the bar of our expectations to cure HIV in future, if not in near future. In this article we would like to throw some light on the phenomenon of HIV infection, treatment, its occurrence as well as a new possibility for its cure, benefits and limitations of this new therapeutic intervention?

UNAIDS is an international agency set up under the umbrella of United Nation which has a mandate to monitor HIV and AIDS infections at global level as well as provide help and support to bring this epidemic to control, while this agency has developed it target to "zero" new infection by the year 2015. Since 1999 it is publishing its annual report about HIV/AIDS epidemic, which is considered as the most authentic document. As per one estimate >90 million individual people has been infected with HIV, till date. UNAIDS Report (2009) estimates more than 34.4 million individuals are living with HIV infections out 34.4 million, children below the age of 15 years account for more than 2.4 million infections. Remaining 31million infected adults are equally shared by men and women, which mean HIV does not discriminate between sexes. On an annual basis, every year more than 2 million individuals get new infections; while 1.8 million die with HIV and AIDS. Nevertheless, risk of vertical transmission (mother to new born baby) of HIV infections has been brought down to only 2% because of better access to anti-retroviral drugs (drugs used for the treatment of HIV infection). As per UNAIDS official report, it monitors incidences of HIV/AIDS in 182 countries throughout the world, out of which only 7 countries are showing increase in incidences of HIV/AIDS compared to year 2001, while in rest of the countries it is either stabilized or towards decline. Still the saddest part of the story is that on a daily basis, globally we are able to provide treatment to only 1 patient a day, while 2 new patients do not get treatment for new HIV infection. For a better understanding of impact of HIV infection, it will be easier to follow the numbers on a daily basis, which comes out to be ~5500 people die every day with HIV/AIDS, while ~7400 people get newly infected on daily basis. This means there is an addition ~1900 new patients everyday to the existing pool of HIV sero-positives, which means the end result of addition of ~0.7 million patients, on annual basis. This is almost equivalent to the number of people living in Stockholm, Sweden or Washinginton, D.C., USA Globally, oceania (in general countries in Australian continent) region is the least affected with HIV infection, while sub-saharan Africa is the worst affected part of this world. ~66% of HIV and AIDS infected people live in this area, still this area have the reputation to have highest incidences of new HIV infections as well as highest rate of death too, which suggest poor health care system as well as ineffective measures to control the HIV menace. In other words, individuals residing in this part of the world simply are unable to bear the cost of treatment, diagnosis and follow-ups, even though various international agencies are providing financial assistance to poor nations, either this money is not enough or not reaching to its beneficiaries. A role of rampant corruption cannot be denied for such an ineffectiveness to control HIV and AIDS infection. As per one estimate an average cost of anti-retroviral treatment is ~US$45000 (more than 1900000 INR for an HIV infected patient in India) patient/year. In developed countries, nowadays an HIV seropositive can live up to 20 years, provided they have an access to proper anti-retroviral treatment. So even, if we remain conservative in our calculation without accounting for any inflation, one patient could easily spend up ~US$ 900,000 (3,80,00000 INR for HIV infected patient in India) only for anti-retroviral treatment to keep control on HIV infection in post HIV infection stages. By any means, that is too exorbitant cost to bear by any patient even in richer societies, what to say about who are underprivileged people, those who are unable to afford two square meals a day. Will they be able to afford medicine, while these are the most vulnerable for HIV infection?

India is also badly affected with HIV and AIDS, while the regulatory bodies for HIV and AIDS is NACO in India with its head office in Delhi and it works in association with UNAIDS regional office in Delhi too. Apart from national offices, every state also has NACO offices. As per the recent report new infections of HIV and AIDS cases in India are on a decline , although knowing the situation in our public health system, it is very difficult to comment about the accuracy of this data. Role of miscalculation in predicting prevalence of HIV infections has been critically evaluated and corrected in UNAIDS Report 2008, which has reduced the numbers of HIV infections drastically. As per the recent report India has more than 2.4 million individual living with HIV infections with a prevalence rate of 0.3%. 170,000 lakh individuals have died with HIV and AIDS, while there is no data about children below the age of 15 years. Somehow in India, HIV and AIDS show regional preferences, as majority of cases are reported from 5 southern states which include Maharashtra, Karnataka, Tamil Nadu, Andhra Pradesh and Kerala. Out of these 5 states Andhra Pradesh is the worst affected, incidences of HIV and AIDS infections are low in northern states. In India majority of cases are from heterosexuals contact except in North Eastern states, where HIV infections are more common among drug abusers. In the recent past, India Today has published a report about increase in HIV/AIDS infection in Punjab due to significant rise in drug abuse among native youth of this state. In summary, in a developing national like India, where more than 50% people live below poverty line, more than 2.4 million cases of HIV/AIDS do not paint a good picture for an incurable infection like HIV.

AIDS was for the first time was detected in 5 gay men from Los Angeles, USA in 1981. At the time neither HIV nor AIDS terms were coined. Only 5 cases of immune-compromised stage was recognized by Center for Disease Control and Preventions (CDC), Atlanta USA which raised the alarm among public health official in USA, they did not go to denial mode like any other country, rather that accepted this is truth and tried all possible efforts to identify the causative organism as well as to find a cure for the unidentified disease. Later, these cases were reported from all over the USA as well as from other parts of the world. The infection was found to affect all races, both sexes and without any discrimination of age. Therefore, vigorous efforts were started to identify the causative organism for such a disastrous disease. In 1983, Luc Montaignier from Pasteur Institute, Paris was the first one to identify the causative organism for this disease for which he was awarded Nobel Prize for Physiology and Medicine in 2008. Montaignier had given the name of this organism as lymphoadenopathy virus (LAV), later Robert Gallo re-confirmed the same virus at National Cancer Institute, USA and gave the name as Human T-cell trophic virus (HTLV). Finally the name Human Immunodeficinecy Virus (HIV) was adopted by International Committee on Taxonomy of Viruses in 1988, since then HIV has become standard name for this virus.

HIV is a virus which belongs to category of viruses known as retroviruses. It is small in size and its genomic structure is also small. HIV simply has 9 genes which produce 15 different proteins, to replicate and to create such havoc. Conventionally, DNA is genetic material for almost all the organisms, except retroviruses, because their genome consist of RNA rather than DNA, which is the reason to name these viruses as "retroviruses". To overcome the problem of transfer of genetic information from one virus to new progeny of virus, these viruses are equipped with a unique enzyme known as reverse transcriptase, which helps to transfer genetic information faithfully by converting viral RNA into cDNA.

Blood is a major component of our immune-system and it consist of different cells types. Lymphocytes are one of them, and our blood has two different types of lymphocytes namely B-lymphocytes and T-lymphocytes. HIV mostly infects T-lymphocytes, because they have CD4 receptors on them. Cd4 is primary receptor for HIV infectivity. There is a normal level of T-lymphocytes in our blood which keeps us healthy by fighting against infections. But in HIV infections, these cells start dying due to active HIV infection and replication leading to reaching dangerously low levels in blood circulation. A significant drop in T-lymphocyes in blood circulation result in immune-deficiency and make the person vulnerable to various infections due to inability of immune-system to defend against infection. This is usually the terminal stage of HIV infection leading to AIDS.

Initial efforts were to control the spread of HIV infection as well as to treat HIV patients. Azidothymidine was 1st drug approved by Food and Drug Administration (FDA), USA to treat HIV infections. This drug inhibits the activity of reverse transcriptase to block HIV replication therefore it reduces production of new viral progeny. Later various effective drugs were developed to treat HIV infections. In the meantime, advances in HIV research were able to provide better understanding about the HIV replication, therefore, various other targets during HIV replication had been tried to block HIV multiplication. These drugs turned out to be highly effective to treat HIV by slowing down HIV replication below detection limit (that means HIV still replicates in patients, but the available diagnostic tests for HIV are unable to detect it). Ultimately, it was concluded that "HIV infections can only be controlled and cannot be cured."

During the course of further studies, it was observed that there are certain individuals who were considered as high risk cases for HIV infections, but they did not get infection of HIV, even though they had been exposed to HIV infections on several occasions. These people were not taking any anti-retroviral treatments too. Some of them lived for almost 30 years since the exposure of HIV infection. This unusual phenomenon lead to a better understanding about HIV infection, which suggested that apart from CD4 receptors (primary receptor for HIV infections), HIV also needs another receptor to enter into host cells, and these are called as co-receptors or chemokine receptors. Chemokines receptors required for HIV infectivity are of two types, CCR5 and CXCR4, on the basis of use of chemokine receptors, HIV viruses were dived into two broad categories R5 and X-4, respectively. It was noticed that individual who had shown natural resistance against HIV infections have mutation (alteration) in their CCR5 co-receptors. Further in depth knowledge suggested that there is a 32 base pair deletion in co-receptor, which is the reason these co-receptors are known as CCR5Δ32/Δ32 (for a better understanding, we know that DNA consists of nucleotide, and each nucleotide is called as one base pair, so in these patient 32 base pairs are missing). This mutation turned out as a "blessing in disguise", as it was the reason in these patients that they do not get infected with HIV. So far, this mutation been noticed only in ~1-3% of Caucasian individuals, and it was not noticed in other races, due to reasons unknown to us. This is an interesting natural phenomenon with clinical implications for HIV treatment. However, it was not put to practice in real life almost 15 years from the date of its discovery. Finally a situation came in Berlin, Germany, which offered a perfect opportunity to try this observation in a real life scenario. There was a 40 year male patient who was infected with HIV for more than 10 years and was being on highly active retroviral treatment (HAART). Obviously, HAART regimen kept HIV below detection limits, but situation took turn for worse and this patient was diagnosed with acute myeloid leukemia (AML). AML is a kind of blood related cancer, so the first choice of treatment for this HIV patient was to treat AML with chemotherapy, however chemotherapy related toxicity compelled to stop HAART in this patient. Stoppage of HAART leads to re-emergence of HIV infections. The patient was running out of luck, because AML chemotherapy did not work very well as well as he was fighting with rebound of HIV infection. Hence, doctors working with the patient started looking for other options, and the only feasible option for him was to go through bone marrow transplantation, being an obvious choice for any patient who is diagnosed with AML.

A panel of doctors did discuss the possible course of treatment for the patient, then Dr. Gero Hutter the hematologist in this team, looked for all the possibilities and suggested that this patient should be transplanted CCR5Δ32/Δ32 allogenic bone marrow, because it had two advantages 1) this kind of mutation in bone marrow are less vulnerable to be rejected by patients' immune system{A condition common among bone marrow transplanted patients}, and 2) because of chemokine receptor mutation, chances are that this patient will not get HIV infection. The whole team agreed with the rationale provided by Dr. Gero Hutter for this patient. An active search for such a donor was started using German Bone Marrow Registry. From this registry, 80 donors were identified who could be probable match for bone marrow transplantation. But donor no. 62 turned out to be a perfect match for this patient as he hadCCRΔ32/Δ32 mutation. Finally the HIV patient was transplanted with donor bone marrow while doctors took all expected precautions. Luckily everything went well as planned, transplant was successful and patient was doing well with no sign and symptoms of HIV, by the time the success of treatment was reported to media and to the world, this HIV seropositive has lived ~2 years post-transplantation without any sign of GVHD as well as HIV replication. It seems like this was a means to achieve cure for HIV, truly it has given a ray of hope for HIV patients. But clinicians and scientists were taking this discovery with some reservations, as there were so many questions, which were difficult to be answered over a short span of two years, and some of those unanswered questions were 1) chimerism {a stage which suggest patient's bone marrow is replaced with donor bone marrow}, 2) vulnerability of patient for HIV infection due to rebound of HIV, 3) activation of HIV from long-lived reservoir cells, etc. Well, the only way to get these answers was to wait and watch the success of this chemokine deficient bone marrow transplanted patient. Everyone was waiting and watching for the outcome of the treatment in relation to HIV infection.

This patient was followed very closely by a team of clinicians and scientists. Finally the report about the success for bone marrow transplantation was declared and results were presented by Dr. Kristina Allers in December 2010. By this time this patient had lived for more than 4 years (i.e., till February, 2011) post-transplantation. Dr. Kristina's group has declared in her report that "Cure for HIV as been achieved". The final outcome of this treatment was far more than satisfactory and this report has answered most of the unanswered questions, if not all of them. This patient has remained HIV free as per all known definitions of HIV infections and diagnostic test which are used in current time. This patient was not any more on any anti-retroviral treatment. The clinical analysis of different types of blood cells suggest that donor's bone marrow has replaced the patient's own bone marrow which means in this patients state of chimerism has been achieved with full success. Tests suggest that there is no evidence for HIV infection in brain, which is very crucial as if it is difficult to treat HIV infections of brain, if not impossible. Mucosal cells (cells which are present on the inner surface of body and considered as a major reservoir for HIV infections) have been shown negative for HIV infection. However, CXCR4 co-receptors are present in this patient, still making him vulnerable for new HIV infection from external source, that is an advice for this patient to be extra careful to avoid any chances to get new infection, although the possibilities can be reduced by prescribing CCR4 antagonist drugs to this patients, in case, if there is any conversion or evolution of X-4 strain of HIV in this patient, that can be brought under control.

Chances are that this treatment modality may become a future possibility to treat HIV patients, before coming to this conclusion we will have to wait and see the outcome from few more cases to affirm the facts. As we know, that there is one major limitation with this modality of treatment is that only a limited number of donors are available to meet the demand of increasing numbers of HIV infections, because this mutation so far has been found only in 1-3% of Caucasians. So far there are no evidences to suggest that natural resistance against HIV also exits among other races, too. Without any doubt there is a need of extensive efforts for identification of this mutation among other races, too. Even though, this treatment could be a blessing for those HIV patients who do not respond to anti-HIV drugs and are terminally ill due to HIV infections. Biomedical sciences also have option for silencing these genes permanently, if these protocols can be optimized, then gene silencing can used to cure HIV with the help of siblings' bone marrow transplantation after permanent silencing of genes of either CCR5 or CXCR4 or even both co-receptor.

Let us hope for the best and wait for the medical and biomedical sciences to raise the curtain of uncertainity prevailing in lives of HIV seropositives and bring a hope of cure for unfortunate HIV victims.