In order to understand where a next breakthrough in HIV/AIDS treatment might be expected, it is necessary to understand the complexity of this viral pathogen and consequently the inherent limitations of the therapeutics that are currently available or could be developed to challenge this disease.
- As we all know, no HIV vaccine is available and considering the characteristics of HIV it is highly unlikely that the existing approaches in vaccine development will ever lead to the production of a working HIV vaccine. The reason lies in the combination of two of the main characteristics of the virus.
A typical vaccine teaches our immune system how to recognise a potential viral pathogen, so that it can immediately identify the intruder and attack it with full force. This way our immune system prevents the virus from silently spreading throughout our body and eventually causing harm to our organism. The HIV virus however primarily targets our T-cells (CD4 and CD8 type), which are key players in our immune system; so that alerting our immune system against HIV, it will mobilize more T cells and consequently bring “more food to the table” for the virus.
Being a retrovirus, HIV also has a very high mutation rate, which means that even if we tought our immune system how to recognise today’s virus, it would probably not immediately recognise the HIV virus of tomorrow, because it has already altered too much.
Current Antiviral drugs
- In such a case, the complexity of HIV’s retroviral replication mechanism offers some additional possibilities to attack the virus, during one of the stages in its reproduction cycle. Many successful anti-retroviral therapies (ART) have been developed over the past decades, where each of them was targeting a specific aspect of HIV reproduction. We now have
drugs that prevent the virus from entering the target cell, called entry-, or fusion inhibitors and two well-known classes of drugs that target the virus once it has entered a cell, preventing it from inserting its viral genetic code into the host cell’s DNA. The first of these inhibitors targets the retrovirus’s necessity to transform its single stranded RNA into a double stranded DNA code capable of being integrated into the host cell’s DNA. This hapens by means of a Reverse Transcription process and HIV brings along its proprietary viral proteins in order to carry out this step. Reverse Transcriptase inhibitors (NRTI, NtRTI and NNRTI’s) target these viral proteins and block the viral retrotranscription process, before a useful piece of proviral DNA is produced. The second class of ART drugs that can protect a host cell from contamination of its DNA are the Integrase Inhibitors. These drugs target the Integrase enzyme necessary for the virus to integrate its proviral DNA into the host cell’s genetic code. If both treatments fail, or if no treatment has been used, the virus will successfully and irreversibly contaminate the host cell, which will in return, sooner or later, start producing new viral particles and this is where real trouble starts. Not only will an infected cell produce from one to ten thousand new virions over its life cycle, it can also remain dormant for an extended period, during which it is virtually impervious to any known antivirus strategy.
Whilst there are several therapeutics available that protect a cell from becoming infected by HIV, there has been up till now only one class of drugs that acts on proviral infected cells by preventing them from producing new, fully functional viral particles. These are the Protease Inhibitors. These inhibitors also target one of the viral proteins; this time the enzyme needed by the virus to aid its proteins in coming to full maturity. With their inhibited protease enzyme, HIV virions remain functionally non-infectious.
HIV Latency & Survival
- As mentioned, HIV is a highly mutative retrovirus with a capability to develop rapid resistance towards any ART thrown against it. The high mutation rate of retroviruses itself is easily explained by the rapid replication rate and the high number of DNA copies retrotranscribed from viral RNA. The retrotranscriptase is prone to error and has no proofreading function, and taking into account that each infected cell in return produces thousands of new virions, it is easy to picture how even within a single infected HIV/AIDS patient, billions of novel virions will emerge which can potentially harbour small variations in their genetic code. ART medications will successfully inhibit most viruses during one of the fundamental steps in their life cycle; however, sooner or later, virions will escape because their viral proteins are just ever so slightly different, carrying with them the genetic qualities that contributed to their survival. If one multiplies this process by the millions it will become clear that rapid resistance development towards traditional ART medication is an inevitable process.
The development of resistance towards ART medication has been mitigated successfully by the combined application of different classes of ART. Such combination therapies have proved to be highly effective in reducing the viral load to a minimum, improving tremendously on the life expectancy of HIV/AIDS patients. Even if incapable of curing the patient, they do keep the disease under control and as such, they currently often talk about HIV management rather than HIV treatment. The success of these Highly Active Anti Retroviral Therapies (HAART) however comes at a price. While each class of antiretroviral compounds is known to have side effects, the combination of two or more in
HAART, as well as potential interactions with other drugs, used to treat concomitant pathologies, has multiplied the risk of side effects and toxicity. These side effects, combined with the fact that HAART patients will need to use these drugs for the rest of their lives, still takes a terrible toll on the quality of life of millions of HIV/AIDS patients under treatment.
Several ART drugs have high molecular weight, lipophilicity and protein binding levels. As such, distribution and delivery throughout the body is not their strongpoint. At least two distinct sections of the human organism, which have a physical barrier that shields them from external influences are known to be impregnable by ART. These are the central nervous system (CNS) and the male testis, both of which known to be latent HIV reservoir sites.
Resistance development against ART
- Through the use of HAART we have come very close to deliver HIV a final blow. Viral loads in blood have become virtually undetectable from time to time, but in the end, the virus always comes back! The reason lies in the fact that HIV hides itself in reservoirs that are completely impervious to ART medications. As mentioned earlier, the CNS and the male testis are the only two physically separated reservoirs in the human body. The other anatomical reservoirs where HIV tends to survive are purely functional and characterised by a very high prevalence of the CD4+ type T-cells and macrophages in which HIV effectively duplicates. It is known that lymph nodes or gastrointestinal mucosa as well as the female reproductive organs are anatomic locations that function as HIV reservoirs.
HIV reservoirs prevent virus eradication in patients receiving HAART. The best picture of a reservoir, without conceiving it as a specific anatomical location, it is rather a pool of resting memory CD4+ T cells carrying latent, but replication-competent proviral genomes.
It is these dormant memory cells, which are, in fact the true big hurdle left in HIV research and in order to challenge this problem, we carried out new strategies with the aim to wake-up these hibernating time bombs. Resting HIV proviral cells can survive for weeks and even up to decades and waking them up in order to eradicate them, it is at present seen as the only solution to the problem. Several approaches are under development, such as the Interleukin 7 Cytokine, but quite predictably, once the dormant cell has been reactivated it still needs to be killed otherwise it will start producing active virions all over again leading in turn to new resting cells. As we have mentioned, only the Protease Inhibitor (PI) class of ART drugs intervenes with new virion production by preventing its essential proteins from reaching maturity. PI treatments do however not lead to cell death (apoptosis) of the reactivated cells. They actually seem to prevent apoptosis and using irony, they help keeping the reactivated CD4+ cells alive. Picture this against a backdrop of already compromised PI functionality, due to resistance development and delivery problems and it will immediately become clear that waking up dormant HIV+ cells is probably not such a good idea, unless accompanied by a valid strategy to eliminate them effectively.