HIV/AIDS research

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]

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]

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]

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.

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.

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.

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.

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.[11] 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."[11]

In 2007, Timothy Ray Brown,[12] 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).[13] 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.[14][15] 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.[15] The virus remained undetectable over three years after the first transplant.[13] Although the researchers and some commentators have characterized this result as a cure, others suggest that the virus may remain hidden in tissues[16] such as the brain (which acts as a viral reservoir).[17] 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.[16][18]

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).[19] 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).[20] 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.[21]

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.[22] 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.[22]

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.[23] 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.[23]

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.[24]

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.[25] 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.[26]

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.[27]

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.[28]

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.[29][30]

In April 2016, Innovative Bioresearch,[31] a privately held company owned by research scientist Jonathan Fior, reported the results of a pioneering pilot study that explored the infusion of SupT1 cells as a cell-based therapy for HIV in a humanized mouse model.[32][33] This novel cell-based therapy uses irradiated SupT1 cells as a decoy target for HIV to prevent CD4+ T cell depletion as well as to render the virus less cytopathic. The research showed that in animals treated with SupT1 cell infusion, significantly lower plasma viral load (~10-fold) and potentially preserved CD4+ T cell frequency were observed at Week 1, with one animal showing complete suppression of viral replication and preservation of CD4+ T cell count (no virus detected anymore at Weeks 3 and 4). As also mentioned in a previous paper written by the same author, Jonathan Fior, in vitro studies of HIV evolution showed that prolonged virus replication in the SupT1 cell line results in a less cytopathic virus with a reduced capacity for syncytium formation, a higher sensitivity to neutralization, improved replication in SupT1 cells and impaired infection of primary CD4+ T cell.[34] According to the research, this indicates that in vivo virus replication in the infused SupT1 cells should also have a vaccination effect.[33]

In March 2019, a patient with Hodgkin's lymphoma was also reported to possibly have been cured using similar treatment to Brown.[35]

• Discovery and development of CCR5 receptor antagonists
• Discovery and development of HIV-protease inhibitors
• Discovery and development of non-nucleoside reverse-transcriptase inhibitors
• Health interventions
• HIV superinfection
• History of HIV/AIDS
• Sex education

• HIV and AIDS News (ScienceDaily)
• HIV and AIDS News (Medical News Today)