HIV/AIDS research

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Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte. HIV-budding-Color.jpg
Scanning electron micrograph of HIV-1, colored green, budding from a cultured lymphocyte.
Diagram of HIV HI-virion-structure en.svg
Diagram of HIV

HIV/AIDS research includes all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as fundamental research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV.

Contents

Transmission

A body of scientific evidence has shown that men who are circumcised are less likely to contract HIV than men who are uncircumcised. [1] Research published in 2014, concludes that the sex hormones estrogen and progesterone selectively impact HIV transmission. [2]

Pre- and post-exposure prophylaxis

"Pre-exposure prophylaxis" refers to the practice of taking some drugs before being exposed to HIV infection, and having a decreased chance of contracting HIV as a result of taking that drug. Post-exposure prophylaxis refers to taking some drugs quickly after being exposed to HIV, while the virus is in a person's body but before the virus has established itself. In both cases, the drugs would be the same as those used to treat persons with HIV, and the intent of taking the drugs would be to eradicate the virus before the person becomes irreversibly infected.

Post-exposure prophylaxis is recommended in anticipated cases of HIV exposure, such as if a nurse somehow has blood-to-blood contact with a patient in the course of work, or if someone without HIV requests the drugs immediately after having unprotected sex with a person who might have HIV. Pre-exposure prophylaxis is sometimes an option for HIV-negative persons who feel that they are at increased risk of HIV infection, such as an HIV-negative person in a serodiscordant relationship with an HIV-positive partner.

Current research in these agents include drug development, efficacy testing, and practice recommendations for using drugs for HIV prevention.

Within-host dynamics

The within-host dynamics of HIV infection include the spread of the virus in vivo, the establishment of latency, the effects of immune response on the virus, etc. [3] [4] Early studies used simple models and only considered the cell-free spreading of HIV, in which virus particles bud from an infected T cell, enter the blood/extracellular fluid, and then infect another T cell. [4] A 2015 study [3] proposes a more realistic model of HIV dynamics that also incorporates the viral cell-to-cell spreading mechanism, where the virus is directly transited from one cell to another, as well as the T cell activation, the cellular immune response, and the immune exhaustion as the infection progresses. [3]

Virus characteristics

HIV binds to immune cell surface receptors, including CD 4 and CXCR4 or CD4 and CCR5. The binding causes conformation changes and results in the membrane fusion between HIV and cell membrane. Active infection occurs in most cells, while latent infection occurs in much fewer cells 1, 2 and at very early stages of HIV infection. 9, 35 In active infection, HIV pro virus is active and HIV virus particles are actively replicated; and the infected cells continuously release viral progeny; while in latent infection, HIV pro virus is transcriptionally silenced and no viral progeny is produced. [5]

Management of HIV/AIDS

Research to improve current treatments includes decreasing side effects of current drugs, further simplifying drug regimens to improve adherence, and determining better sequences of regimens to manage drug resistance. There are variations in the health community in recommendations on what treatment doctors should recommend for people with HIV. One question, for example, is determining when a doctor should recommend that a patient take antiretroviral drugs and what drugs a doctor may recommend. This field also includes the development of antiretroviral drugs.

Age acceleration effects due to HIV-1 infection

Infection with the Human Immunodeficiency Virus-1 (HIV) is associated with clinical symptoms of accelerated aging, as evidenced by increased incidence and diversity of age-related illnesses at relatively young ages. A significant age acceleration effect could be detected in brain (7.4 years) and blood (5.2 years) tissue due to HIV-1 infection [6] with the help of a biomarker of aging, which is known as epigenetic clock.

Long-term nonprogressor

A long-term nonprogressor is a person who is infected with HIV, but whose body, for whatever reason, naturally controls the virus so that the infection does not progress to the AIDS stage. Such persons are of great interest to researchers, who feel that a study of their physiologies could provide a deeper understanding of the virus and disease.

HIV vaccine

An HIV vaccine is a vaccine that would be given to a person who does not have HIV, in order to confer protection against subsequent exposures to HIV, thus reducing the likelihood that the person would become infected by HIV. Currently, no effective HIV vaccine exists. Various HIV vaccines have been tested in clinical trials almost since the discovery of HIV.

Only a vaccine is thought to be able to halt the pandemic. This is because a vaccine would cost less, thus being affordable for developing countries, and would not require daily treatment. [7] However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine. [7] [8]

In 2003 a clinical trial in Thailand tested an HIV vaccine called RV 144. In 2009, the researchers reported that this vaccine showed some efficacy in protecting recipients from HIV infection (31% efficacy). Results of this trial give the first supporting evidence of any vaccine being effective in lowering the risk of contracting HIV. Other vaccine trials continue worldwide including a mosaic vaccine using an adenovirus 26 vector [9] as well as a newer formulation of RV144 called HVTN 702. [10]

One recent trial was conducted by scientists at The Scripps Research Institute (TSRI) who found a way to attach HIV-fighting antibodies to immune cells, creating a HIV-resistant cell population. [11]

Microbicides for sexually transmitted diseases

A microbicide for sexually transmitted diseases is a gel which would be applied to the skin - perhaps a rectal microbicide for persons who engage in anal sex or a vaginal microbicide for persons who engage in vaginal sex - and if infected body fluid such as blood or semen were to touch the gel, then HIV in that fluid would be destroyed and the people having sex would be less likely to spread infection between themselves.

On March 7, 2013, the Washington University in St. Louis website published a report by Julia Evangelou Strait, in which it was reported that ongoing nanoparticle research showed that nanoparticles loaded with various compounds could be used to target infectious agents whilst leaving healthy cells unaffected. In the study detailed by this report, it was found that nanoparticles loaded with Mellitin, a compound found in Bee venom, could deliver the agent to the HIV, causing the breakdown of the outer protein envelope of the virus. This, they say, could lead to the production of a vaginal gel which could help prevent infection by disabling the virus. [12] Dr Joshua Hood goes on to explain that beyond preventive measures in the form of a topical gel, he sees "potential for using nanoparticles with melittin as therapy for existing HIV infections, especially those that are drug-resistant. The nanoparticles could be injected intravenously and, in theory, would be able to clear HIV from the blood stream." [12]

Stem cell transplantation

In 2007, Timothy Ray Brown, [13] a 40-year-old HIV-positive man, also known as "the Berlin Patient", was given a stem cell transplant as part of his treatment for acute myeloid leukemia (AML). [14] A second transplant was made a year later after a relapse. The donor was chosen not only for genetic compatibility but also for being homozygous for a CCR5-Δ32 mutation that confers resistance to HIV infection. [15] [16] After 20 months without antiretroviral drug treatment, it was reported that HIV levels in Brown's blood, bone marrow, and bowel were below the limit of detection. [16] The virus remained undetectable over three years after the first transplant. [14] Although the researchers and some commentators have characterized this result as a cure, others suggest that the virus may remain hidden in tissues [17] such as the brain (which acts as a viral reservoir). [18] Stem cell treatment remains investigational because of its anecdotal nature, the disease and mortality risk associated with stem cell transplants, and the difficulty of finding suitable donors. [17] [19]

Stem cell based gene therapy

In the past 7 years, scientists have been using different approaches of stem cell based gene therapy in an attempt to develop a cure as well as to propose an alternative to the conventional antiretroviral therapy (ART). [20] Specifically, advances had been made with a cure to HIV.

A cellular receptor, generally CCR5 or CXCR4 is required in order for HIV entry into CD4 cells. Cells of individuals homozygous for the CCR5 gene variant Δ32 (CCR5Δ32/Δ32) lack the CCR5 cell-surface expression, meaning that they are naturally resistant to infection with CCR5 tropic HIV strains (R5 HIV). [21] One study done in 2011 achieves successful CD4+ T-cell reconstitution as a result of CCR5Δ32/Δ32 stem cell transplantation at the systemic level and in the gut mucosal immune system in a patient with HIV. Additionally, it provides evidence for the reduction in the size of the potential HIV reservoir over time. The patient in this study even remained HIV free without any evidence of having it for more than 3.5 years. [22]

Other theoretical cures to HIV-1 have been proposed. One supposed cure to HIV-1 involves the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem cells and progenitor cells (GM-HSPC). Though this study does involve several early stage clinical trials that have demonstrated the safety and feasibility of this technique only for HIV-1, none have resulted in improvement of the disease state itself. [23] Therefore, this strategy is intended to go alongside already existing treatment techniques such as drugs and vaccines. However, future technology regarding this approach of single treatment cell therapy could potentially replace current therapy altogether as a functional or sterilizing cure to HIV-1. [23]

An additional study involves the use of genetically engineered CD34+ hematopoietic stem and progenitor cells. Experimental long-term in vivo HIV gene therapy have had huge issues due to both transduction ending in multiple copies of heterologous DNA in target cells as well as low efficacy of cell transduction at the time of transplantation. This study demonstrated the efficacy of a transplantation approach that ultimately allows for an enriched population of HSPCs expressing a single copy of a CCR5 miRNA. [24] Since positive selection of modified cells is likely to be insufficient below the threshold they found of at least 70% of the HIV target cells resulting in gene modification from efficient maintenance of CD34+ T cell and a low viral titer, the findings show evidence that clinical protocols of HIV gene therapy require a selective enrichment of genetically targeted cells. [24]

Immunomodulatory agents

Complementing efforts to control viral replication, immunotherapies that may assist in the recovery of the immune system have been explored in past and ongoing trials, including IL-2 and IL-7. [25]

The failure of vaccine candidates to protect against HIV infection and progression to AIDS has led to a renewed focus on the biological mechanisms responsible for HIV latency. A limited period of therapy combining anti-retrovirals with drugs targeting the latent reservoir may one day allow for total eradication of HIV infection. [26] Researchers have discovered an abzyme that can destroy the protein gp120 CD4 binding site. This protein is common to all HIV variants as it is the attachment point for B lymphocytes and subsequent compromising of the immune system. [27]

New developments

A turning point for HIV research occurred in 2007, following the bone marrow transplant of HIV sufferer Timothy Ray Brown. Brown underwent the procedure after he developed leukaemia and the donor of the bone marrow possessed a rare genetic mutation that caused Brown's cells to become resistant to HIV. Brown attained the title of the "Berlin Patient" in the HIV research field and is the first man to have been cured of the virus. As of April 2013, two primary approaches are being pursued in the search for a HIV cure: The first is gene therapy that aims to develop a HIV-resistant immune system for patients, and the second is being led by Danish scientists, who are conducting clinical trials to strip the HIV from human DNA and have it destroyed permanently by the immune system. [28]

Three more cases with similarities to the Brown case have occurred since the 2007 discovery; however, they differ because the transplanted marrow has not been confirmed as mutated. Two of the cases were publicized in a July 2013 CNN story that relayed the experience of two patients who had taken antiretroviral therapy for years before they developed lymphoma, a cancer of the lymph nodes. They then underwent lymphoma chemotherapy and bone marrow transplantation, while remaining on an antiretroviral regimen; while they retained traces of HIV four months afterwards, six to nine months after the transplant, the two patients had no detectable trace of HIV in their blood. However, the managing clinician Dr. Timothy Heinrich stated at the Malaysian International AIDS Society Conference where the findings were presented:

It's possible, again, that the virus could return in a week, it could return in a month -- in fact, some mathematical modeling predicts that virus could even return one to two years after we stop antiretroviral therapy, so we really don't know what the long-term or full effects of stem cell transplantation and viral persistence is. [29]

In March 2016, researchers at Temple University, Philadelphia, reported that they have used genome editing to delete HIV from T cells. According to the researchers, this approach could lead to a dramatic reduction of the viral load in patient cells. [30] [31]

In March 2019, a patient with Hodgkin's lymphoma was also reported to possibly have been cured using similar treatment to Brown. [32]

See also

Related Research Articles

HIV Human retrovirus, cause of AIDS

The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of blood, pre-ejaculate, semen, and vaginal fluids. Research has shown that HIV is untransmittable through condomless sexual intercourse if the HIV-positive partner has a consistently undetectable viral load. Non-sexual transmission can occur from an infected mother to her infant during pregnancy, during childbirth by exposure to her blood or vaginal fluid, and through breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells.

Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit its development.

HIV vaccine development In-progress vaccinations that may prevent or treat HIV infections

An HIV vaccine could be either a preventive vaccine or a therapeutic vaccine, which means it will either protect individuals from being infected with HIV or treat HIV-infected individuals. And it could either induce an immune response against HIV or consist of preformed antibodies against HIV.

The management of HIV/AIDS normally includes the use of multiple antiretroviral drugs in an attempt to control HIV infection. There are several classes of antiretroviral agents that act on different stages of the HIV life-cycle. The use of multiple drugs that act on different viral targets is known as highly active antiretroviral therapy (HAART). HAART decreases the patient's total burden of HIV, maintains function of the immune system, and prevents opportunistic infections that often lead to death. HAART also prevents the transmission of HIV between serodiscordant same sex and opposite sex partners so long as the HIV-positive partner maintains an undetectable viral load.

The spread of HIV/AIDS has affected millions of people worldwide; AIDS is considered a pandemic. The World Health Organization (WHO) estimated that in 2016 there were 36.7 million people worldwide living with HIV/AIDS, with 1.8 million new HIV infections per year and 1 million deaths due to AIDS. Misconceptions about HIV and AIDS arise from several different sources, from simple ignorance and misunderstandings about scientific knowledge regarding HIV infections and the cause of AIDS to misinformation propagated by individuals and groups with ideological stances that deny a causative relationship between HIV infection and the development of AIDS. Below is a list and explanations of some common misconceptions and their rebuttals.

Protease inhibitors (PIs) are a class of antiviral drugs that are widely used to treat HIV/AIDS and hepatitis C. Protease inhibitors prevent viral replication by selectively binding to viral proteases and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.

CCR5

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.

Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function, health care and co-infections as well as viral genetic variability may affect the rate of progression to the point of needing to take medication in order not to develop AIDS.

HIV/AIDS Spectrum of conditions caused by HIV infection

Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection a person may not notice any symptoms, or may experience a brief period of influenza-like illness. Typically, this is followed by a prolonged period with no symptoms. If the infection progresses, it interferes more with the immune system, increasing the risk of developing common infections such as tuberculosis, as well as other opportunistic infections, and tumors which are otherwise rare in people who have normal immune function. These late symptoms of infection are referred to as acquired immunodeficiency syndrome (AIDS). This stage is often also associated with unintended weight loss.

Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) co-infection is a multi-faceted, chronic condition that significantly impacts public health. According to the World Health Organization (WHO), 2 to 15% of those infected with HIV are also affected by HCV, increasing their risk of morbidity and mortality due to accelerated liver disease. The burden of co-infection is especially high in certain high-risk groups, such as intravenous drug users and men who have sex with men. These individuals who are HIV-positive are commonly co-infected with HCV due to shared routes of transmission including, but not limited to, exposure to HIV-positive blood, sexual intercourse, and passage of the Hepatitis C virus from mother to infant during childbirth.

HIV superinfection is a condition in which a person with an established human immunodeficiency virus infection acquires a second strain of HIV, often of a different subtype. These can form a recombinant strain that co-exists with the strain from the initial infection, as well from reinfection with a new virus strain, and may cause more rapid disease progression or carry multiple resistances to certain HIV medications.

Long-term nonprogressors (LTNPs), sometimes also called elite controllers, are individuals infected with HIV, who maintain a CD4 count greater than 500 without antiretroviral therapy with a detectable viral load. Many of these patients have been HIV positive for 30 years without progressing to the point of needing to take medication in order not to develop AIDS. They have been the subject of a great deal of research, since an understanding of their ability to control HIV infection may lead to the development of immune therapies or a therapeutic vaccine. The classification "Long-term non-progressor" is not permanent, because some patients in this category have gone on to develop AIDS.

Gero Hütter is a German hematologist. Hütter and his medical team transplanted bone marrow deficient in a key HIV receptor to a leukemia patient, Timothy Ray Brown, who was also infected with human immunodeficiency virus (HIV). Subsequently, the patient's circulating HIV dropped to undetectable levels. The case was widely reported in the media, and Hütter was named one of the "Berliners of the year" for 2008 by the Berliner Morgenpost, a Berlin newspaper.

Timothy Ray Brown First person known to have been cured of HIV/AIDS

Timothy Ray Brown was an American considered to be the first person cured of HIV/AIDS. Brown was called "The Berlin Patient" at the 2008 Conference on Retroviruses and Opportunistic Infections, where his cure was first announced, in order to preserve his anonymity. He chose to come forward in 2010. "I didn't want to be the only person cured," he said. "I wanted to do what I could to make [a cure] possible. My first step was releasing my name and image to the public."

The Berlin patient is an anonymous person from Berlin, Germany, who has exhibited prolonged "post-treatment control" of HIV viral load after HIV treatments were interrupted.

A small proportion of humans show partial or apparently complete inborn resistance to HIV, the virus that causes AIDS. The main mechanism is a mutation of the gene encoding CCR5, which acts as a co-receptor for HIV. It is estimated that the proportion of people with some form of resistance to HIV is under 10%.

Sharon Lewin

Sharon Ruth Lewin, FRACP, FAHMS is an Australian Infectious Disease physician and researcher, and the inaugural director of The Peter Doherty Institute for Infection and Immunity, a joint venture between the University of Melbourne and the Royal Melbourne Hospital. She leads a multi-disciplinary research team working on mechanisms of HIV latency, clinical trials advancing potential HIV cure strategies and how HIV is affected by co-infections such as Hepatitis B. Lewin has extensive experience in scientific leadership, and is a strong advocate for community engagement and partnership in research.

Julianna Lisziewicz is a Hungarian immunologist. Lisziewicz headed many research teams that have discovered and produced immunotheraputic drugs to treat diseases like cancer and chronic infections like HIV/AIDS. Some of these drugs have been successfully used in clinical trials.

Since antiretroviral therapy requires a lifelong treatment regimen, research to find more permanent cures for HIV infection is currently underway. It is possible to synthesize zinc finger nucleotides with zinc finger components that selectively bind to specific portions of DNA. Conceptually, targeting and editing could focus on host cellular co-receptors for HIV or on proviral HIV DNA.

A therapeutic vaccine is a vaccine which is administered after a disease or infection has already occurred. A therapeutic vaccine works by activating the immune system of a patient to fight an infection. A therapeutic vaccine differs from a prophylactic vaccine in that prophylactic vaccines are administered to individuals as a precautionary measure to avoid the infection or disease while therapeutic vaccines are administered after the individual is already affected by the disease or infection. Therapeutic vaccine fights the existing infection in the body rather than immunizing the body for protection against future diseases and infections. The therapeutic vaccines are mostly against viral infections. The patients affected with chronic viral infections are administered with therapeutic vaccines, as their immune system is not able to produce enough efficient antibodies.

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