HIV/AIDS Prophylaxis

Prophylaxis is the term used to describe medicinal attempts to prevent, rather than treat or cure a disease.

There are now a number of treatment options available for people who believe they have been accidentally exposed to HIV to reduce the risk of infection. There are also drugs available which can reduce the risk of the transmission  from an infected mother to her baby during childbirth.

Contributions of non human primate studies to the use of HIV drugs to prevent infection

Since the early days of the HIV pandemic, as soon as it was clear that an effective HIV vaccine would still be years away, there has been considerable interest in using anti-HIV drugs to reduce the risk of infection following exposure to HIV (so-called prophylaxis). Animal models of HIV infection, especially the rhesus macaque, have played a major role in developing and testing these treatments.

The development of HIV drugs to treat HIV-infected persons has shown that many compounds that are effective in vitro (i.e., in tissue culture assays) fail to hold their promise when tested in humans, because of unfavorable pharmacokinetics, toxicity or insufficient antiviral efficacy. The same principles apply to the development of drugs to prevent HIV infection. The outcome of drug administration is determined by many complex interactions in vivo between the virus, the antiviral drug(s) and the host; with current knowledge, these interactions cannot be mimicked and predicted sufficiently by in vitro studies or computer models.

Testing different compounds in human clinical trials is logistically difficult, time-consuming and expensive, so only a very limited number of candidates can be explored in a given time. Fortunately, the development of antiviral strategies can be accelerated by efficient and predictive animal models capable of screening and selecting the most promising compounds. No animal model is perfect and each model has its limitations, but the simian immunodeficiency virus (SIV) of macaques is currently considered the best animal model for HIV infection because of the many similarities of the host, the virus and the disease. Non-human primates are phylogenetically the closest to humans, and have similar immunology and physiology (including drug metabolism, placenta formation, fetal and infant development). In addition, SIV, a virus closely related to HIV-1, can infect macaques and causes a disease that resembles HIV infection and AIDS in humans, and the same markers are used to monitor the disease course. For these reasons, SIV infection of macaques has become an important animal model to test antiviral drugs to prevent or treat infection.

Different nonhuman primate models have been developed based on the selection of the macaque species, the particular SIV strain and the inoculation route (e.g. IV injection, vaginal exposure) usedANCHOR. These models have been improved and refined during the past two decades. For example, SIV-HIV chimeric viruses have been engineered to contain portions of HIV-1, such as the enzyme reverse transcriptase (“RT-SHIV”) that the virus requires in order to multiply or the envelope protein (“env-SHIV”) that the virus needs if it is to escape from a cell and infect other cells, to allow these models to also test drugs that are specific for HIV-1 reverse transcriptase or envelopeANCHOR .ANCHOR

Many studies in non-human primates have investigated whether the administration of anti-HIV drugs prior to or just after exposure to virus can prevent infection. The earliest studies indicated that drugs such as the reverse transcriptase inhibitor zidovudine (AZT), the first approved drug treatment for HIV, were not very effective in preventing infection, but a likely reason for this was the combination of a high-dose viral inoculums used, the direct intravenous route of virus inoculation, and the relative weak potency of drugs at that timeANCHOR ANCHOR ANCHOR ANCHOR ANCHORThe proof-of-concept that HIV drugs can prevent infection was demonstrated in 1992 when a 6-weeks zidovudine regimen, started 2 hours before an intravenous low-dose virus inoculation that more accurately represented HIV infection in humans, protected infant macaques against infectionANCHOR. These results were predictive of a subsequent clinical trial (Pediatric AIDS Clinical Trials Group Protocol 076), which demonstrated that zidovudine administration to HIV-infected pregnant women beginning at 14 to 34 weeks of gestation, and continuing to their newborns during the first 6 weeks of life reduced the rate of viral transmission by two-thirdsANCHOR.

Since then, a growing number of studies have been performed in macaques to identify more effective and simpler prophylactic drug regimens. These studies generally used lower virus doses, sometimes combined with a mucosal route of virus inoculation that mimics vaginal or anal exposure responsible for the majority of human HIV infections. These studies demonstrated that administration of some newer anti-HIV drugs, including the reverse transcriptase inhibitors adefovir (PMEA), tenofovir (PMPA), and emtricitabine (FTC) that prevent the virus from multiplying in the infected cell, and the CCR5 inhibitor CMPD167 that stops the virus from binding the CCR5 receptor on the cell surface and entering a cell in the first place, starting prior to, or at the time of virus inoculation, was able to prevent infection, though with varying success ratesANCHOR ANCHOR ANCHOR ANCHOR ANCHOR, ANCHOR ANCHOR ANCHOR. Only very few compounds such as the reverse transcriptase inhibitors tenofovir, BEA-005 and GW420867, and the CCR5 inhibitor CMPD167, were able to reduce infection rates when treatment was started after virus inoculation. For those drugs that were successful in post-exposure prophylaxis studies, a combination of the timing and duration of drug administration was found to determine the success rate, because a delay in the start, a shorter duration, or interruption of the treatment regimen all reduced the prophylactic efficacyANCHOR ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR information that has guided the design of subsequent clinical trials.

While some of the compounds such as GW420867 that showed prophylactic efficacy in the macaque model are no longer in clinical development (e.g., due to toxicity or pharmacokinetic problems discovered later in pre-clinical testing), the very promising results achieved with tenofovir have sparked further studies aimed at simplifying the prophylactic regimen. Several studies in infant and adult macaques have demonstrated that short or intermittent regimens of tenofovir (with or without coadministration of emtricitabine) consisting of one dose before and one dose after each virus inoculation were highly effective in reducing SIV infection ratesANCHOR ANCHOR ANCHOR.

The demonstration at the beginning of the 1990’s that anti-HIV drugs can prevent infection in macaques has provided the rationale to administer these compounds to humans to reduce the likelihood of infection in several clinical settings. Antiviral drugs are now recommended, usually as a combination of several drugs, to reduce the risk of HIV infection after occupational exposure (e.g., needle-stick accidents of health care workers) and non-occupational exposure (e.g. sex or injection-drug use)ANCHOR ANCHOR. As mentioned previously, drug regimens containing zidovudine and more recently also more potent drugs such as nevirapine have proven to be highly effective in reducing the rate of mother-to-infant transmission of HIV, including in developing countriesANCHOR ANCHOR ANCHOR and save many thousands of lives every year . Because the short nevirapine regimen that is given to pregnant HIV-infected women at the onset of labor frequently induces drug resistance mutations in the mother that may compromise future treatmentANCHOR, tenofovir’s high prophylactic success in the infant macaque model has sparked clinical trials in which a short tenofovir-containing regimen was added to existing perinatal drug regimens to reduce the occurrence of resistance mutations and / or further lower the transmission rate ANCHOR ANCHOR ANCHOR ANCHOR ANCHOR.

Because an efficacious HIV vaccine has so far not been identified, the concept of using pre-exposure prophylaxis also as a possible HIV prevention strategy in adults has gained rapid momentum in recent years.  The promising prophylactic data of tenofovir (with or without emtricitabine) in the macaque model, combined with the favorable pharmacokinetics, safety profile, drug resistance pattern and therapeutic efficacy of these drugs in HIV-infected people, have pushed these compounds into front-runner position in ongoing clinical trials that investigate whether uninfected adults who engage in high-risk behavior will have a lower infection rate by taking a once daily tablet of tenofovir or tenofovir plus emtricitabine. The results of these ongoing trials are highly anticipated. An overview of the design, status and challenges of these trials which are currently underway at several international sites and target different high-risk populations can be found on the website of the AIDS Vaccine Advicacy CoalitionANCHOR ANCHOR.

In conclusion, nonhuman primate models of HIV infection have played an important role in guiding the development of pre- and post-exposure prophylaxis strategies. Ongoing comparison of results obtained in these models with those observed in human studies will allow further validation and refinement of these animal models so they can continue to provide a solid foundation to advance our scientific knowledge and to guide clinical trials

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Examples of research studies in the news

 

06/07/18 HIV vaccine on horizon as jab triggers immunity in humans and stops monkeys being infected

 

 

09/03/18 Monkeys reveal new clues toward elusive HIV vaccine and cure

 

Several AIDS vaccines have had some success in monkey models, which typically use SIV, a simian cousin of HIV that causes AIDS in rhesus macaques. But one vaccine has long stood out from the pack. Designed by Louis Picker and colleagues at Oregon Health & Science University’s Vaccine and Gene Therapy Institute in Beaverton, the vaccine stitches SIV genes into a harmless Trojan horse, cytomegalovirus. Picker’s team has given the vaccine to more than 200 monkeys and then “challenged” them with injections of a particularly nasty strain of SIV. All told, 55% of the animals became temporarily infected and then completely controlled the virus for years or even cleared it. Two stubborn questions remain, however: Picker and co-workers have yet to nail down the immune responses that explain the vaccine’s success, and they also can’t explain why it frequently fails.

 

http://www.sciencemag.org/news/2018/03/monkeys-reveal-new-clues-toward-elusive-hiv-vaccine-and-cure

 

22/09/17 New antibody attacks 99% of HIV strains

 

Scientists have developed an antibody that attacks 99 per cent of HIV strains. Already tested on monkeys, trials on human beings could begin next year. Up until now, HIV has been difficult to treat because of its ability to mutate and change its appearance. However, the study, published in the journal Science, combines three broadly neutralising antibodies capable of targetting HIV viruses, into an even more powerful "tri-specific antibody" that attacks three key parts of the virus. This molecule is more potent and has greater breadth than any single naturally occurring antibody that's been discovered. This makes it harder for the virus to evade the antibodies. Experiments on 24 monkeys showed none of those given the tri-specific antibody developed an infection when they were later injected with the virus.

 

http://www.bbc.com/news/health-41351159 

 

14/10/16 Promising HIV therapy 

 

A new therapy for HIV shows promise in monkeys. A combination of drugs was able to protect rhesus macaques for two years from SIV - the monkey (simian) version of HIV. The combination included standard antiretroviral drugs and combined it with an experimental antibody.
 
http://www.independent.co.uk/news/science/hiv-cure-breakthrough-monkeys-humans-vedolizumab-primate-a7361146.html

 

22/07/16 Researchers used mice to show that SIV can transmit from chimps to human cells

 

Certain strains of the Simian Immunodeficiency Virus (SIV) are able to infect humans. This evidence suggests that the disease which affects chimpanzees may be the original source of HIV in humans. It is believed that humans who ate infected bush meat was the source of the disease. The researchers used humanised mice and found the SIV strains were able to infect them easily.

 

http://www.dailymail.co.uk/sciencetech/article-3703161/Forms-HIV-carried-chimpanzees-infect-HUMANS-Evidence-supports-theory-AIDS-epidemic-started-primates.html

 

19/05/16 HIV DNA removed from infected rats and mice

 

Gene-editing technology has allowed scientists to remove HIV DNA from various organs of infected mice and rats. This research could lead to an outright cure. A similar study involving a larger group of animals will be conducted before clinical trials in humans can take place.

http://www.independent.co.uk/news/science/hiv-aids-cure-virus-disease-dna-genes-temple-university-research-gene-editing-a7037571.html

 

21/03/16 Giving antibodies to infant macaques exposed to HIV-like virus could clear the infection

 

An infant rhesus macaques treated with antibodies within 24 hours of being exposed to SHIV (simian HIV) was completely cleared of the virus researchers at Oregon National Primate Research Center found. SHIV-infected non-human primates can transmit SHIV to their offspring through milk feeding, just as humans can transmit HIV from mother to child through breastfeeding and during childbirth. In humans, a combination of measures for mothers and infants, including antiretroviral therapy (ART), C-section delivery and formula feeding, have decreased the rate of mother-to-child HIV transmission from 25% to less than 2% since 1994. However, despite this decrease, approximately 200,000 children are infected with HIV each year worldwide, primarily in developing countries where ART is not readily available. Whilst it is recommended to treat human babies with ART during the last month of gestation, the few days after delivery, and during breastfeeding time frames, risks still remain, including toxicities associated with long-term ART use, the development of drug-resistant viral variants, and lack of access to prenatal care prior to delivery. This discovery indicates that using new methods, such as antibodies, to limit infection after exposure in newborns could be advantageous.

http://www.ohsu.edu/xd/about/news_events/news/2016/03-21-giving-antibodies-to-inf.cfm

 

21/01/16 A protein found in primates and humans may stop HIV progression

 

A protein found in both primates and humans may stop HIV progression and switch on the immune system, according to a  new study published January 14 in the journal, Heliyon. TRIM5α from the rhesus macaque (TRIM5αRh) is a restriction factor that shows strong activity against HIV-1

http://www.alnmag.com/news/2016/01/protein-part-treats-hiv-infections-non-human-primates
http://www.heliyon.com/article/e00056/

 

22/10/15  Designer antibodies may rid body of AIDS virus

 

Anti-HIV drugs halt the symptoms of the disease but have never eliminated completely the virus from anyone. HIV is very good at evading all our defences, by residing in the cells that are looking for it – LT4 white blood cells. Two new studies show that artificial antibodies could ‘redirect’ the immune response to these latently infected cells and help drain those HIV reservoirs in the body. Although these in vitro studies have been successful, work is now underway in monkey models.

 

http://news.sciencemag.org/biology/2015/10/designer-antibodies-may-rid-body-aids-virus

 

13/10/15 AIDS pioneer brings AIDS vaccine to clinic

 

A new AIDS vaccine trial will commence in the USA, developed over 15 years by Robert Gallo, the scientist who discovered the link between HIV and AIDS in 1984. A phase 1 clinical trial is being conducted in 60 volunteers and will test the safety and immune responses of the vaccine, therefore it will take a while before we know if it is more effect than the other 100+ AIDS vaccines that have been trialled over the past 30 years but so far extensive testing in monkeys has proven successful.

http://news.sciencemag.org/health/2015/10/aids-pioneer-finally-brings-aids-vaccine-clinic 

 

03/07/15 New AIDS vaccine protects 50% of monkeys against SIV

 

A new AIDS vaccine protects Monkeys against SIV. With a 50% success rate in monkeys with SIV, the vaccine is already being trialled in humans. The researchers hope that the vaccine will work better in humans than in monkeys, given that the monkeys had been given a gigantic dose of SIV, much more than average people get in an average sexual exposure to HIV. HIV vaccines have been proven many times unsuccessful because the virus infects the same cell the body uses to fight against the infection, it changes a lot so becomes hard to recognise and the human body doesn’t seem to create powerful broadly neutralizing antibodies against the virus. This new vaccine uses a common cold virus called adenovirus 26 that activates an immune response. Then a second vaccine is given with bits of HIV attached. The immune system cells will also "see" the attached bit of HIV and, the researchers hope, react against any HIV virus should the vaccinated person ever be exposed.

 

http://www.nbcnews.com/health/health-news/new-aids-vaccine-protects-monkeys-n385751

 

12/03/15 ‘cellular scissors cut out HIV from infected human cells

 

Scientists found a way to cut out HIV from infected human cells with ‘cellular scissors’. They have been customising a defence system used by bacteria and training this scissor-like machinery to recognise the HIV virus. The method successfully cut HIV’s genes, inactivating the virus. This technique could completely remove HIV from up to 72% of human cells that had been infected with HIV, even in a dormant state.

 

http://www.dailymail.co.uk/sciencetech/article-2990549/Could-cure-HIV-Scientists-way-cut-virus-infected-areas-cellular-scissors.html

 

27/02/15 Llamas are immune to HIV - new hope for a vaccine

 

Llamas might be the new hope for a new AIDS vaccine or treatment – llamas appear to be immune to HIV. Llama antibodies, which develop in response to the virus potently neutralizes more than 95% of HIV strains. In humans, the antibodies are completely ineffective at halting the virus they have evolved to target. Unlike human antibodies, llama antibodies have a single chain of proteins, which allows them to accurately aim at specific viruses compared to a more scatter-gun approach to the human immune system, attacking all foreign viruses.

 

http://www.usatoday.com/…/lima-peru-llama-aids-hiv/23884381/

 

19/02/15 A new gene therapy vaccine seems to completely protect monkeys from HIV

 

A new approach to vaccination seems to completely protect monkeys from HIV. Vaccines usually prepare the immune system to fight an infection. Instead, scientists have altered the DNA of monkeys to give their cells HIV-fighting properties. This technique uses gene therapy to introduce a new section of DNA – containing the instruction to build tools to neutralize HIV - inside healthy muscle cells. The monkeys who received the injection were protected from all types of HIV for at least 34 weeks. Researchers want to start human trials as fast as possible and they believe that this approach may be useful in people who already have HIV.

 

http://www.bbc.co.uk/news/health-31511244

 

05/02/15 Novel concept for HIV and cancer vaccines - incorporating antigenic diversity

 

Novel concept for HIV and cancer vaccines – incorporating antigenic diversity into it. Conventional vaccines are based on total antigens, but the high variability of some pathogens allows them to escape recognition by the immune system. The research group proposed that an HIV vaccine should be able to induce both humoral and cellular responses – the main defence mechanisms against pathogens – and that a cancer vaccine should reduce tumour growth and metastasis by the activation of lymphocytes T. Faced with the antigenic diversity and the enormous variability of the pathogens and cancer cells, the researcher suggested the construction of vaccines based on Variable epitope (small fragments of an antigen) libraries. This would induce broadly neutralizing serum in mice against the pathogens and cancer cells. The results of the research group are highly promising as a universal concept for the generation of vaccines against antigenically variable pathogens and cancer.

http://www.alphagalileo.org/ViewItem.aspx?ItemId=149417&CultureCode=en

 

02/12/14 HIV evolving to be milder

 

A study from the University of Oxford has shown that the HIV virus is evolving into a ‘milder’ form, taking longer to trigger AIDS in patients. Some virologists even suggest that the virus may become almost harmless as it continues to evolve. SIV, the primate version of HIV, is less dangerous for those species than HIV is to us- possibly showing this effect in another species:

 

http://www.bbc.co.uk/news/health-30254697

 

 

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41. PrEP Watch,  http://www.prepwatch.org/

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• Animal(s): Primates
• Research field(s): Disease characteristics, Drugs and toxins, Infection and Immunity

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Last edited: 4 March 2021 14:20