“Countdown to a Cure for AIDS” is a research initiative by amfAR AIDS foundation, aimed at finding a broadly applicable cure for HIV by 2020. Infected person is considered cured if he meet three criteria: 1) be able to live a normal, healthy lifespan; 2) be off antiretroviral therapy or any other HIV-related medications; and 3) be incapable of transmitting the virus to others. “The Berlin Patient,” reported cured and group of patients in France reported to be in sustained remission, have created hope of cure for HIV. These cases coupled with the availability of new and emerging technologies, and improved economy led us to believe that cure is possible and it will bring the global AIDS epidemic to an end. Several factors influence the effectiveness of a cure, including how long the person has been infected; the route of infection; the person’s age when he or she acquired HIV, as well as current age; how soon they started antiretroviral therapy; and whether they have opportunistic infections or other HIV-related health problems. Effective anti-retroviral treatment for HIV prevents spread of HIV from mother-to-child and from infected person to non-infected one. Also it can prevent transmission after potential exposure to the virus (post-exposure prophylaxis) and taking treatment prior to exposure to HIV can also reduce one’s risk of contracting the virus (pre-exposure prophylaxis).  However AIDS pandemic cannot be ended with treatment alone because very few people globally are on treatment, many people don’t know their HIV status and many people don’t get tested due to stigma associated with HIV.

Keywords: AIDS; Cure; Treatment  

According to WHO estimates, 35.3 million people are living with HIV worldwide with over 1.6 million deaths and 1.6 million infected suggesting that the HIV epidemic continues to be a major scientific challenge. Of the estimated 6,300 new infections per day, 95% occur in low-middle income countries [1]. “Countdown to a Cure for AIDS” is a research initiative aimed at finding a broadly applicable cure for HIV by 2020. There is widespread agreement among researchers that a cure for HIV is possible due to improving economy, recent technological advances and momentum in the research community. Since 30 years amfAR has been at the forefront of HIV/AIDS research, and was the first organization to aggressively pursue cure-focused HIV research. In 2010, the Foundation launched the amfAR Research Consortium on HIV Eradication (ARCHE), which supports collaborative teams of scientists at leading research institutions around the world in a directed effort to explore potential strategies for eliminating HIV infection [2].

Is Cure Possible?

First case Timothy Brown who was considered as cured of HIV was reported in 2008, also known as Berlin patient. HIV was eradicated from his body through a stem cell transplant using cells immune to HIV. Then the news of cure of a young child in Mississippi who was given medication shortly after being born with HIV came. The other two men were also cured through a stem cell transplant, but using cells not immune to HIV. Also a cohort of 14 patients in France was reported to be in sustained remission (still HIV positive, but off treatment for several years with no sign of disease progression). Hence, 18 people till day have been declared functionally cured of HIV. These and other advances have created a groundswell of optimism about the prospects for a cure. This has led us to believe that now is the time to mount an all-out effort to find a cure and finally bring the global AIDS epidemic to an end [3].

Definition of Cure:

There are two basic types of AIDS cure: functional cure and sterilizing cure. The definition of a “functional HIV cure” is that people living with the virus no longer have to take medicine and they remain healthy and non-infectious, whether or not every trace of HIV has been removed from their body. A “sterilizing” cure is one that removes all traces of HIV from a person’s bodies. It is possible to have functional cure and all 18 patients above mentioned were functionally cured.  Hence an infected person would need to meet three criteria to be considered as cured: 1) be able to live a normal, healthy lifespan; 2) be off antiretroviral therapy or any other HIV-related medications; and 3) be incapable of transmitting the virus to others. However, several factors influence the effectiveness of a cure, including how long the person has been infected; the route of infection; the person’s age; how soon antiretroviral therapy started; and presence of opportunistic infections or other HIV-related health problems [2,4].

Challenges in HIV Cure:

1.       Chart the precise locations of viral reservoirs that persist in the body;
2.       Understand how HIV persists in the reservoirs;
3.       Record how much virus they hold; and
4.       Eliminate the virus [2,4]

Role of Effective anti-Retroviral HIV Treatment in Cure:

Anti-retroviral therapy keeps people with HIV healthy, prevent the spread of the virus from mother-to-child and reduce the chance of transmission of HIV to non-affected people by 96%. Treatment can also serve as prevention in people not living with HIV. However, complete eradication of the virus from the body is not possible as the virus resides in ‘latent reservoirs’ within memory CD4+ T cells and cells of the macrophage–monocyte lineage [5,6]. The cells that harbor latent HIV are typically concentrated in specific anatomic sites, such as secondary lymphoid tissue, testes, liver, kidney, lungs, gut and the CNS [5]. The eradication of the virus from such reservoirs is critical to the effective long term treatment of HIV/AIDS patients. When taken within 72-hours after potential exposure to the virus, HIV treatment can prevent transmission. This tactic is called “PEP” for “post-exposure prophylaxis.” Taking treatment prior to exposure to HIV can also reduce one’s risk of contracting the virus. This approach is called “PrEP” for pre-exposure prophylaxis. However it is not possible to end the AIDS pandemic through treatment alone due to various reasons. Too few people globally are on treatment, many people don’t know their HIV status. In “window period” they could get a false negative test result but still be positive. Therefore, there could always be people living with the virus who aren’t aware they have it unless they are repeatedly tested. Also the stigma surrounding HIV makes people, understandably, afraid to get tested and treated for HIV. Hence it is evident that ART is not a long-term solution for HIV-infected individuals. Besides the deleterious side effects, ART does not eradicate HIV and does not optimally reconstitute the immune system [7, 8].

“Shock and Kill” Strategy:

Scientists are working on drugs that could be used to “shock” HIV out of latent reservoirs so that it can be “killed” by antiretroviral treatment or by the immune system. Several molecules currently tested in clinical trials to reactivate HIV from latently-infected CD4+ T cells have demonstrated promising results and could influence the selection, expansion, persistence and function of HIV-specific CD8+ T cell to kill HIV reservoir [9,10]. These molecules include HDACis (histone deacetylase inhibitors) like valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA), or antibodies to block negative regulators. HDACis increased histone acetylation in CD8+ T cells and restored their ability to differentiate into functional memory cells capable of immediate cytokine production and providing protective immunity [11]. Targeting Negative Regulators like PD-1, CD160 and 2B4 restore T cell proliferation, cytokine production and thus effector function. Studies suggest that ART along with blocking antibodies for PD-1 signaling might prove to be more potent in increasing CD8+ T cell killing of latently infected cells and preventing reactivated virus from re-infecting new CD4+ T cells [12,13].

Newer Drugs for Functional Cure:

Cortistatin A, isolated from a marine sponge Corticium simplex has been shown to inhibit Tat. The protein tat amplifies HIV replication by tremendously accelerating the rate of DNA transcription in the cell and ensures that a productive infection is initiated and maintained. Tat also ensures to reactivate the virus when ART is stopped in people with a viral load undetectable by even the most sensitive tests. Scientists from the Florida campus of The Scripps Research Institute (TSRI) have shown that Cortistatin A reduces residual levels of virus from infected dormant cells, establishing a near-permanent state of latency and greatly diminishing the virus capacity for reactivation. The new configuration, didehydro-Cortistatin A (dCA) inhibits replication in HIV-infected cells by significantly reducing levels of viral mRNA – the blueprints for producing proteins and more infection. Therefore, dCA combined with ART would be aimed at halting ongoing viral replication, reactivation, and replenishment of the latent viral reservoir. Hence, it could induce a further stage of viral decay such that eventually there was no residual HIV replication left, and possibly even no cells capable of producing HIV, possibly culminating in the sterilizing cure [14,15].

Nanotechnology for HIV/AIDS Treatment

The use of nanotechnology platforms for delivery of drugs is revolutionizing medicine in many areas of disease treatment [16]. Nanoscale delivery systems can enhance half-lives of ART, keeping them in circulation at therapeutic concentrations for longer periods of time and also
enhance and modulate the distribution of hydrophobic and hydrophilic drugs into and within
different tissues due to their small size. Targeted delivery of antiretroviral drugs to CD4+ T cells and macrophages and delivery to brain and other organ systems could ensure that drugs reach latent reservoirs [17,18]. Nanosuspensions (200 nm) of the drug rilpivirine (TMC278)

 
Gene Therapy

One promising alternative approach for HIV cure is gene therapy, in which a gene is inserted into a cell to interfere with viral infection or replication. Other nucleic acid-based compounds, such as DNA, siRNA, RNA decoys, ribozymes and aptamers or protein-based agents such as fusion inhibitors and zinc-finger nucleases can also be used to interfere with viral replication [24,25]. Early efforts in gene therapy for HIV/AIDS have been focused on viral vectors as the delivery agents and scientist reported that cell-derived gene transfer is safe and biologically active in HIV-infected individuals. However, use of viral vectors for gene delivery poses fundamental problems such as toxicity, immunogenicity, insertion mutagenesis and limitations with scale-up procedures [26, 27]. Hence investigation of nonviral vectors for gene delivery has been encouraged, where nanotechnology platforms are showing great promise [26, 27]. In recent years, the Nobel prize-winning discovery of RNA interference (RNAi) in 1998 by Fire, Mello and colleagues has gained much attention in the clinical therapeutics field and it is also considered to have therapeutic potential for HIV/AIDS [24, 25]. RNAi can either target the various stages of the viral replication cycle or various cellular targets involved in viral infection such as CD4, CCR5, and/or CXCR4, the major cell surface co-receptors responsible for viral entry [28]. Single-walled nanotubes were shown to deliver CXCR4 and CD4 specific siRNA to human T-cells and peripheral blood mononuclear cells [29].

Immunotherapy for HIV/AIDS

Immunotherapy is a treatment approach involving the use of immunomodulatory agents to modulate the immune response against a disease. The major effect of an infection by HIV is the loss of CD4+ T cells leading to profound immunosuppression, manifested by the presence of dysfunctional B-cells, natural killer cells and the macrophages in chronically HIV-infected patients [30]. The various immunotherapy approaches for HIV/ AIDS could be based on delivering cytokines (such as IL-2, IL-7 and IL-15) or antigens [30, 31]. During HIV infection, IL-2 and IL-15 is down regulated, while IL-7 levels are increased. Extensive phase I and II studies demonstrated that IL-2 increases the frequency of naïve and central memory (TCM) CD4+ T cells, as well as CD8+ cytotoxic functions. However, phase III clinical trials demonstrated that IL-2 increased CD25 and FOXOp3 expression (and thus regulatory T cells), which was associated with increased risk of opportunistic diseases [26, 27]. Stimulation of cells from HIV-infected subjects with IL-15, enhances the frequency of effector memory CD8+ T cell, promotes their survival and cytotoxic functions [32, 33]. IL-7 regulates T-cell maturation and supports peripheral T cell homeostasis. Phase I/II trials demonstrated that the administration of IL-7 was able to restore circulating CD4 T-cell counts as well as the frequency of CD8+ T cells, without any effect on the number of regulatory T cells [34]. Administration of IL-15 during the contraction phase (7–14 days) and not during the expansion phase could have a better effect in the enhancement of HIV-specific CD8+ T cells response after vaccination.

Vaccination Strategies for Control of HIV:

The major obstacle to HIV eradication is the persistence of latent proviral reservoirs that are not targeted by antiretroviral regimens [35, 36]. Eradication strategy aims at the induction of viral replication in latently-infected cells and at the elimination of these reactivated cells by either direct cytolytic targeting or by immunotherapeutic intervention [37]. Recent studies suggested that initiating ART in early HIV infection could lead to control of HIV replication control in 5% to 15% of individuals after analytical treatment interruption (ATI) [38, 39, 40]. Early and prolonged ART has been shown to be associated with an HIV-specific CD8+ T cell cytokine profile comparable to that of long-term non-progressors [41]. HIV-specific CD8+ T cells play a crucial role in mediating antiviral immunity by killing the productively infected CD4+ T cells [42]. Novel CD8 T cell-based vaccine strategies are therefore needed to increase the number and function of HIV-specific CD8+ T cells that could control viral rebound after ART cessation, with the ultimate goal of achieving spontaneous control of viral replication without treatment [43].

Hence, researchers suggests that cure to HIV is possible. Studies are going on in various fields like anti-retroviral drugs, newer promising drugs like Cortistatin A and histone deacetylase inhibitors. Researchers are also working on newer techniques of drug delivery such as nanotechnology. In addition to these, gene therapy, immunotherapy and vaccination strategies are newer modalities for functional cure in HIV. The path of HIV cure has been difficult, and a still challenging road is ahead, but there has been considerable progress in the recent past.

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