Current State of HIV Research

Current State of HIV Research
Mar-01-2016 0 comments Cube Biosystems

It's not difficult to state with absolute certainty what has been the most groundbreaking development in the management and treatment of HIV to date. It has been, of course, the use of antiretroviral drugs, which have been hugely successful at minimizing HIV blood levels and enabling those infected to not only live relatively 'normal' lifestyles, but also enjoy a long, healthy life, with a life expectancy roughly equal to that of Americans without the virus. However, introduction of new antiretrovirals peaked in 1996, and while we've been continuing with dedicated research into HIV and its treatments, there has not, as yet, been the significant announcement we've been hoping for - a cure. So just where are we in terms of HIV research, what advances have we seen lately, and are we any closer to attaining that ultimate goal?

Source: HHMI

Understanding the Virus

Perhaps some of the biggest noise in the preclinical world has been about how we're starting to understand more about how the virus 'operates' within the body. A great deal of research has been undertaken in the preclinical field to delve into the finer details, with the potential for these findings to directly influence future clinical advances. To date, one of the most prominent factors that has been established is that there are three very large challenges we face when it comes to eradicating HIV in its entirety.

The first challenge that has been discovered is this; we now know that HIV spreads in two significantly different ways. It spreads through simple replication, but it also spreads through cell to cell transmission. Research has shown that while antiretroviral drugs are successful in killing off the 'free virus', they're not quite as effective at stopping the spread of HIV from an infected cell to a healthy cell. Therefore, while antiretrovirals can effectively manage HIV blood levels, they cannot remove the virus completely.

For effective drug delivery, nanoparticles must not only evade the immune system, but be able to specifically target cell types.
Scanning electromicrograph of an HIV-infected T cell.
Source: NIAID

The second challenge that experts are currently facing is that HIV has been discovered 'hiding' in reservoirs - most notably in the lymphatic tissue - much like certain cancers. While it can appear that the virus has been successfully eradicated, low levels of HIV that are 'hiding out' can replicate rapidly. The virus remains suppressed throughout treatment, but can bound back when medication is stopped. Unfortunately, this is relatively common, with a 50 to 70 percent non-adherence rate for antiretrovirals.

The final challenge we're facing is in relation to gender differences, which is an area that's largely unexplored in terms of HIV. Reports suggest that less than 25 percent of participants in HIV medical trials are women, and concerns have been raised that there is the potential for major differences in both pharmacokinetics and pharmacodynamics between men and women. Currently, we are very limited in how much we can learn about eradicating the virus should treatment responses differ significantly.

HIV has been put on the back burner. So, for the time being, we need to keep using antiretrovirals as a primary treatment. However, as we know, antiretrovirals are not completely effective. There are many issues surrounding their use, including non-adherence and the potential for resistance. The World Health Organization notes that 'no antiretroviral drug is resistance-proof', and that, at some point, 'HIV drug resistance will evolve naturally' which is a point of particular concern. Unfortunately, this has begun. We have already seen a resistance to tenofovir-based antiretrovirals.

Advances in HIV Medications

Experts are confident that at least two areas should benefit from nanotechnology in medicine; oncology and immunodeficiency. In terms of oncology, we are already seeing biodegradable polymers such as PEG, PVP, dextran, and chitosan being used as methods for delivering cancer drugs to animals. If we can safely apply similar techniques to humans, we'll be able to successfully change the way we treat certain cancers. One concept that's getting experts excited, for example, is the idea that we could target cancer stem cells using phenformin, delivered in a polymer carrier that ensures the enzymes do not break down before the polymer has burrowed into a 'leaky', defective cell, thereby reducing toxicity to healthy cells.

Currently, antiretroviral drugs are the only approved method for managing HIV in the United States. Antiretroviral therapy involves a combination of drugs from up to six distinct categories; nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists, protease inhibitors, entry inhibitors, and integrase strand transfer inhibitors. As HIV evades the immune system, vaccine trials and other proposed methods for managing the virus have largely proven to be unsuccessful, as the immune system has been unable to recognize its intended target. However, when we look at recent developments in HIV medications, we can see that these are areas that are rapidly expanding, and it's these areas that are expected to be a major focus of HIV research moving forward.

HIV Vaccine Research

Scientists have been attempting to create an effective HIV vaccine since 1987, with the first large scale trial in the United States taking place in 1998. Perhaps the most successful attempt was with HVTN 505 in 2009, which the National Institute of Allergy and Infectious Diseases stopped administering in 2013 due to poor outcomes. Despite clear issues in terms of logistics, vaccines are still a major focus moving forward, especially as we're currently relying upon what is a relatively small amount of approved drugs.

Immunotherapies, which have already been approved for use on some cancers, involve DNA-based vaccines utilizing isolated neutralizing antibodies, which are capable of stimulating an immune response from systems that are unable to recognize their target. While this form of therapy has not yet been approved for widespread usage across the infected population, the first human study, which took place within the last few years, has clearly demonstrated significant changes in HIV blood levels and has reportedly been well tolerated by participants. Longevity of the effects is so far unclear, and appears to be largely based on individual sensitivity to the antibodies. The longest reduction in HIV blood levels was reported to last for 28 days, which signals hope for improving adherence to HIV medications.

Viral vectors are another avenue that is being explored, once again 'tricking' the immune system into activating in response to the largely undetectable virus. Generated proteins are secreted throughout the body, instructing the immune system to target the HIV virus. So far, we've seen a number of viral vector vaccines enter Phase III trials, such as the ALVAC vector (the 'Thai Trial') which reported a 31.2 percent success rate in preventing spreading of HIV, but there have also been a number of setbacks with viral vectors. As the World Health Organization notes, trials using Adenovirus 5 as the vector have largely proven to be unsuccessful, and may even have contributed towards increasing HIV blood levels.

Further Advances in HIV Research

Along with the development of HIV vaccines, another major focus of HIV research going forward is a continuation of the work that is already being carried out in order to better understand how the virus works, and how - if at all - it can effectively be controlled by means other than antiretroviral drugs. Recently, there has been research that suggests that m6A modifications to RNA could hold the clue to replication of the virus. A team from the University of California in San Diego have claimed that HIV replication levels vary significantly, depending on whether enzymes add m6A to RNA, or remove it. It is hoped that this information may be able to be utilized pharmacologically to develop effective drugs.

We're also expecting to see a dedicated focus on neutralizing antibodies, such as VRC01, which are already showing promising, yet somewhat restricted, early results. Based on these advances, in the future, we can fully expect to find success with a range of treatments other than antiretroviral drugs. We should, however, be prepared for these therapies to be used in conjunction with existing management methods, rather than as standalone techniques. Many in the field are stating that a combination approach to effective management is likely to be the most realistic scenario, at least for now, rather than a single 'miracle cure', despite some organizations such as the Foundation for Aids Research aiming to find a cure by the year 2020. It seems somewhat optimistic based on the current state of HIV research, but it's important to remember that HIV was once a death sentence. Now, those infected with HIV are able to lead happy and relatively healthy lives. Anything is possible.

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