SARS-CoV-2 may be the virus that is dominating your news apps and tv screens right now, but it certainly is not the only virus causing issues on a global scale. HIV (Human Immunodeficiency Virus) was first identified in 1983 and although new infections are on the decline, it still poses a huge risk to global health. There are currently around 40 million people living with HIV with approximately 1.7 million new infections occurring every year. Unfortunately, unlike COVID-19, we have not managed to create a successful vaccine (or four) to target HIV, meaning that the main course of action has been to treat new infections rather than prevent them. However, this could be changing.
Back in 2007, whilst carrying out a screen of the peptides present in human semen, Munch et al discovered that seminal fluid contains protein fragments that aggregate to form amyloid fibrils. Amyloid fibrils are large, insoluble polypeptides that form from the coming together of smaller protein fragments. They are implicated in a wide variety of diseases, such as Alzheimer’s, infections, and diseases related to prions (small pathogenic proteins). It was shown that there are three main protein fragments in seminal fluid that aggregate to form amyloid fibrils; these are prostatic acid phosphatase (PAP), and semenogelin 1 and 2. The fibrils formed were termed SEVI (semen-derived enhancer of viral infection) and SEM1/2, respectively. At this point you are probably wondering what the link is between these random semen-derived proteins and HIV, right? Interestingly, further analysis showed that these fibrils drastically increased the rate of HIV infection. In instances where the fibrils were present, a much lower viral titre was required in order to establish infection.
The method by which SEVI and SEM1/2 fibrils do this is strangely simplistic. Such fibrils are coated in positive charges as a result of containing many positive amino acids, making them cationic (possessing a positive surface charge). In 2009, Roan et al demonstrated that it is this cationic nature that underpins the mechanism of HIV infection enhancement. The positively charged amyloid fibril acts a bridge between the HIV virion and target immune cell, both of which are negatively charged. This works to overcome the repulsion between the negative charges and mediates membrane fusion and viral entry into the cell. This mechanism is incredibly effective at increasing the rate of HIV transmission and is well-suited to work with the structure of the HIV virion, due to the relatively low number of spike surface proteins (gp120) on the viral envelope. This makes it easier for the amyloid fibrils to access the viral envelope and consequently mediate viral and target cell membrane fusion. The discovery of this method of infection enhancement has wide-scale potential for re-modelling the way we prevent new HIV infections, as these protein fibrils provide a novel target for potential antimicrobial therapies. If we can find a molecule that successfully inhibits the interaction between these fibrils and HIV then it could be used in topical creams to be applied prior to sexual intercourse to hopefully reduce the rate of viral transmission. This holds great promise, as heterosexual transmission via seminal fluid remains the dominant mode of HIV-1 transmission, especially in areas where HIV-1 infections are most prevalent (such as Sub-Saharan Africa). Therefore, interfering with this semen-derived process could greatly reduce infection rates.
HAART (highly active antiretroviral therapy) is currently the main therapeutic route to treat and reduce HIV infection. It works by using a combination of anti-retroviral drugs to inhibit HIV replication and subsequently delay the or prevent the progression of HIV to AIDS (acquired immune deficiency syndrome). The use of a cheap, accessible therapeutic agent such as a topical cream is made even more attractive when you consider the fact that a lot of antiretroviral drugs used to treat HIV do not penetrate the seminal fluid in the same way that they do the blood. This means that they potentially do not reduce viral titre in semen to the same degree as the rest of the body. Along with this, there are issues with adherence to HAART (as it is a life-long treatment option), and resistance to treatment is also an emerging problem. Therefore, there is a persistent need for new routes of therapy, such as one that targets the SEVI and SEM1/2 fibrils mentioned above.
There are of course many things to consider when looking into potential new drugs to target these proteins. As of yet there is not a huge amount of research out there into the natural role of these proteins. A small number of studies have suggested a link between semen-derived amyloid fibrils and fertility, and have also shown them to play a role in directing the immune response to target non-viable sperm cells that make their way into the female reproductive tract. All of this suggests that these fibrils may play important roles in natural processes within the body, meaning that any potential drugs would need to not have any negative effects on these processes in order to be successful. Hopefully, emerging research will reveal novel antimicrobial drugs that have the potential to take on the HIV/AIDS epidemic from a new angle.
1. https://www.sciencedirect.com/science/article/pii/S0092867407012846 ‘Semen-Derived Amyloid Fibrils Drastically Enhance HIV Infection’ – Munch et al 2007, DOI: https://doi.org/10.1016/j.cell.2007.10.014
2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2612336/ ‘The Cationic Properties of SEVI Underlie Its Ability To Enhance Human Immunodeficiency Virus Infection’ – Roan et al 2009, DOI: https://dx.doi.org/10.1128%2FJVI.01366-08
3. Röcker, A., Roan, N.R., Yadav, J.K., Fändrich, M., and Münch, J. (2018). Structure, function and antagonism of semen amyloids. Chemical Communications 54, 7557–7569. DOI: https://doi.org/10.1039/C8CC01491D