|Year : 2011 | Volume
| Issue : 3 | Page : 461-464
Cure for HIV: New possibility on horizon
Anchal Singh1, Udai Pratap Singh2, Ajit Varma3, Ashish Swarup Verma2
1 Department of Microbiology and Immunology, Kirskville College of Osteopathic Medicine, A. T. Still University, Kirsksville, MO 63501, USA; Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector-125, NOIDA- 201 303, Uttar Pradesh, India
2 Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector-125, NOIDA- 201 303, Uttar Pradesh, India
3 Amity Institute of Microbial Technology, Amity University Uttar Pradesh, Sector-125, Noida-201303, Uttar Pradesh, India
|Date of Web Publication||3-Sep-2011|
Ashish Swarup Verma
Amity Institute of Biotechnology, Amity University Uttar Pradesh, Sector-125, NOIDA- 201 303, Uttar Pradesh, India
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Singh A, Singh UP, Varma A, Verma AS. Cure for HIV: New possibility on horizon. J Pharm Bioall Sci 2011;3:461-4
Certain infectious diseases have devastating impact on human population, because these diseases spread rapidly and cause death to a large numbers of people. No matter how dangerous these diseases are, no matter which part of the world they spread, and no matter which populations they affect, there is always a subset of human beings who survive. The reason behind mankind's continuous existence and survival is "immunity." Those human beings who survive even with the worst form of infectious disease can be called as "spared" human beings. In other words, this phenomenon is known as "natural resistance." These humans are spared because of two possible reasons: (i) they develop immunity against the disease, e.g., milk maids do not get small pox, and (ii) somehow these human beings are inherently resistant to disease, e.g., HIV infections. Existence of natural resistance opens new avenues to formulate new strategies, which can be used to shield other individuals, who do not have resistance against the disease/s. Spaniards are burning example of natural resistance. Spaniards were resistant to small pox, while Aztecs were not, and probably resistance among Spaniards helped them to win war against Aztecs in South America.  Similar kind of observation was also reported in case of HIV infections, almost a decade after the discovery of HIV. "Natural resistance" was observed in a cohort of high-risk Caucasian individuals as they were reported to have resistance against HIV infections. 
Gottlieb et. al. (1981) had reported Pneumocystis carinii pneumonia (PCP) in gay men from Los Angeles, USA.  But in 1981, either HIV or AIDS terms did not exist. Later, PCP patients were confirmed with HIV infections. This was the first documented report about HIV. Luc Montagnier from France and Robert Gallo from USA separately identified the causative organism for this disease as a retrovirus, although both of them have given different names to the same virus. Later, the term acquired immunodeficiency syndrome (AIDS) was adopted by Centre for Disease Control and Prevention, Atlanta, USA (CDC) in 1982. 
In 1987, for the first time, Azidothymidine (Azt), a reverse transcriptase inhibitor was approved by Food and Drug Administration (FDA), USA to treat HIV patients.  Initial success of Azt to treat HIV infection brought so much enthusiasm and optimism among health care community, that Ms. Margret Heckler, Secretary, Human Health Services, USA in 1984 announced that a preventive vaccine against HIV will be there in next two years!!!  Still, the truth is that neither any vaccine nor any drug is effective enough to cure HIV. Fact remains, "HIV infection can be only be controlled and cannot be cured."
CD4 receptors are the primary receptor for HIV infection. With this information, scientists artificially tried to infect laboratory mouse with different HIV strains. However, efforts to infect mouse with HIV turned out to be futile. Absence of co-receptors in mouse is one of the main reasons, behind the failure of HIV infectivity to mouse model. These studies further focused on the role of co-receptors for HIV infections. It was concluded that CD4 receptors alone are not enough for HIV infections as HIV also needs co-receptor. Co-receptors for HIV infection are known as chemokine receptors. CXCR4 and CCR5 are the two main co-receptors for HIV infections, and expressions of these co-receptors vary from cell type to cell type. This is one of the reasons that different strains of HIV have shown variable cellular susceptibility.
Success of HIV infection is dependent upon attachment of HIV on CD4 receptors with subsequent binding of HIV to co-receptor/s. R5 strain of HIV bind with CCR5, while X-4 strain of HIV binds via CXCR4.  Therefore, it can be hypothesized that individuals who lacks CCR5 gene should be resistant to HIV infections. This hypothesis was supported by the observation that some people who failed to show HIV infectivity even though they are categorized as high-risk cases. , This observation is one of the shining examples for "natural resistance" against HIV, which has enormous clinical significance. Certainly, it was a very significant observation for an incurable infection like HIV. In theory, it was presumed that these patients may have low levels of HIV infection, which could be the reason for failure to establish HIV infections among these individuals. But in vitro studies have confirmed that even high concentrations of HIV failed to infect these cells, which are the experimental evidences for natural resistance against HIV infections. 
Detailed studies revealed a better understanding about the role of co-receptors for non-infectivity of HIV. Individual who are heterozygous for mutant co-receptors show HIV infectivity, but progression of HIV was very slow compared to individuals with normal levels of co-receptors. However, people who are homozygously mutant for co-receptors (CCR5) are completely resistant to HIV infections, because they do not get infected with HIV. These alleles are known as Δ32 /Δ32 for CCR5 (32-bp deletion). In case of homozygous deletion of CCR5, it results in an inactive CCR5 gene product, which confers high resistance against HIV infection. Prevalence of CCR5 mutations is ~1-3% in western population, and unfortunately, so far, these mutations are observed in only Caucasians. ,
Individuals with these mutation remained alive and free from HIV infections for >10 years, some even remained infection free >30 years, even though they were not under any anti-retroviral treatments.  So, the bottom line is that these individuals remained disease-free or in other words these individuals have natural resistance against HIV. This conclusion gets extra strength with the fact that some of these individuals have been exposed to HIV infections on many occasions, but they remained free of HIV.  This phenomenon has offered an excellent model to revisit HIV infectivity. These observations suggest possible implication of stem cells or bone marrow stem cells transplantation as a new hope to cure HIV infections.
But the real test of this observation to cure HIV with success was reported in the February 2009 issue of New England Journal of Medicine.  It was just a coincidence that a 40-year-old male who was HIV positive for more than 10 years was diagnosed with acute myelogenous leukemia (AML) in Germany. This patient was under highly active anti-retroviral treatments (HAART) with no signs and symptoms of HIV or AIDS. Therefore, this patient was tried with two courses of induction chemotherapy and one course of consolidation therapy for AML. During chemotherapeutic intervention, due to toxicity of chemotherapy, HAART was stopped. Discontinuation of HAART lead to viral rebound, ultimately HAART was resumed, which brought HIV replication again below detection limits within three months of resumption of HAART. In these circumstances, the obvious course of treatment for this patient was bone marrow transplantation and bone marrow transplantation was tried. Physician searched the German Bone Marrow Donor Center registry for human leukocyte antigen (HLA) matching of bone marrow to perform bone marrow transplantation. For HLA matching, 80 donors were identified in registry. Dr. Hutter, hematologist working with this patient, has taken an extra consideration to search and select a donor, who is carrying homozygous mutation for CCR5, i.e., Δ32/Δ32. Luckily donor number 62 turned out to be a good option as this donor met both criteria, i.e., HLA match along with Δ32 mutation, and fortunately this donor agreed to donate bone marrow. The bone marrow transplantation was performed twice in this patient, the second transplantation was performed after 390 days of first bone marrow transplantation. Second bone marrow transplantation was performed due to relapse of AML. This patient was followed for 20 months post transplantation.
Transplanted patient was monitored closely on regular basis for HIV infections. Patient remained HIV seronegative up to 20 months, even though anti-retroviral treatments were discontinued just a day before first transplantation, which means this patient after transplantation of Δ32/Δ32 CCR5 bone marrow did not have any rebound of HIV, even though this patient was HIV seropositive prior to bone marrow transplantation. This patient was healthy for almost two years and did not show any signs of relapse of HIV, but a possibility of viral relapse cannot be denied at this moment, however only time will tell the story. This patient turns out to be negative for viral RNA as well as pro-viral DNA. The more interesting feature of this transplantation is that this patient showed shift from CCR5 to homozygous Δ32/Δ32 CCR5. A closer analysis of rectal biopsy suggests that macrophages in mucosal area still belonged to CCR5-positive cells, which failed to show any proviral DNA. So far this clinical case suggests that one can halt HIV replication by replacing majority of cells resistant to HIV infections.
| Concerns|| |
Loss of HIV infectivity in HIV seropositive is due to transplantation of mutant cell type is a clear cut evidence for possible application of this approach to treat HIV patients, still the question is "Is this patient cured from HIV?" It is too early to come to this conclusion, as there are so many possibilities that can only be predicted at this time, such as: (i) cells of different parts of body like brain, gut, liver, kidney and heart, which are not replaced still may have HIV, therefore chances are this virus to reemerge in future,  (ii) HIV tropism is also a concern, as this patient is only negative for CCR5, so it could be resistant to R5 strain specifically, but a possibility of re-establishment of X-4 strain of HIV cannot be denied as this patient has CXCR4 receptor. Although it is a common observation that X-4 HIV strain does not emerge in preserved/restored immune system, but there are reports about re-emergence of X-4 strain of HIV among Δ32 CCR5 individuals. 
Is bone marrow transplantation a viable course of treatment for HIV seropositives? Arguments are: (i) When we weigh the pros and cons of bone marrow transplantation in HIV seropositive or pros and cons of anti-retroviral treatment, ideally bone marrow transplantation do not overweigh the benefits compared to anti-retroviral treatment, (ii) immunosuppressive treatment are the basic requirement for successful bone marrow transplantation, which could be a real risk for HIV patients as they may create life threatening situation, as well as reemergence of HIV infection, and (iii) ablation of immune cells is a risky procedure.
| Future Possibilities|| |
This clinical report has certainly opened up new vista to explore new approaches to find a cure for HIV. At present, we have so many options available, which can be tried to evaluate their efficacy on HIV infections. Some of other viable choices are: (i) target cells modification without eliminating host bone marrow, which could possibly be helpful to control HIV infection in case of already infected patients, e.g., development of vectors specific for leukocytes, which can modulate CCR5 expression either transiently or stably, and (ii) specific siRNA, antisense RNA or ribozyme can also be used to reduce expression of CCR5. ,
So far absence of any sign of HIV replication in bone marrow transplanted long-term survivor of HIV infection has offered a hope towards a cure for HIV. Pros and cons of bone marrow transplantation in case of a cure for HIV have been recently discussed.  Combination of various approaches can help to find a better solution to cure HIV infection. "Will it become a reality?", to have a definitive answer for this question, we will have to wait for time to tell us the story!!!
| Acknowledgments|| |
Authors are thankful to Prof. A. K. Srivastava, DG, AIB, Amity University Uttar Pradesh, India, for providing necessary resources and facilities for completion of this manuscript. Authors are also grateful to Mr. Dinesh Kumar for his secretarial assistance.
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