Mayte Coiras
Immunopathology and Viral Reservoir, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain
Antiretroviral treatment (ART) has represented a very important advance for people with HIV (PWH) since it has transformed a potentially fatal disease into a chronic situation. ART consists of a combination of medicines that are directed against specific targets of HIV life cycle, thereby impeding viral replication and the production of new viral particles that may disseminate the infection through the organism. Therefore, the start of ART is recommended as soon as possible after diagnosis because it would permit PWH live longer and healthier, and it reduces the risk of transmission of HIV to other people.
However, although ART may prevent infection of new target cells, it cannot eliminate the cells that have already been infected before starting ART. These cells belong to our immune system, and they form part of specific subsets of memory cells that are long-lived cells with capacity to keep memory against past infections. Once HIV infects these cells, they may not die due to the infection, but they return to a resting, latent state so they cannot be detected by other cells of the immune system that would destroy them. In these cells, called the viral reservoir, the virus remains hidden in the form of a provirus that is integrated in the cellular chromosomes, and is unaffected by both the immune system and ART. The viral reservoir is formed very fast after infection and nowadays the only way to impede its formation is the Pre-exposure Prophylaxis (PrEP) in non-infected people, which may reduce the risk of HIV infection from sexual contact by about 99%, although it is no so effective to reduce the risk from drug injection (estimated as 74%). PrEP is really ART taken by people not infected with HIV to prevent the infection, but it is important to have into account thar PrEP does not protect against other infections such as herpes virus, gonorrhea, syphilis, or chlamydia, that are also sexually transmitted.
Consequently, the viral reservoir constitutes the main obstacle for PWH to be cured with ART alone. It has been determined that more than 70 years of ART would be necessary to cure HIV infection. Therefore, PWH should take ART for life. This calculation was performed assuming that all cells that form part of the viral reservoir contain proviruses that are transcriptionally silent, which means that they cannot reactivate to produce new viral particles unless the cell is activated again. However, recently it has been determined that a significant part of the reservoir is in fact transcriptionally active even in the presence of ART, and so the infected cells are continuously producing viral proteins and small quantities of virus that remain undetectable by usual diagnostic techniques. This would permit the immune system to detect and eliminate only those cells from the viral reservoir that contain these active, competent proviruses, resulting in a selection mechanism induced by the immune system and maintained by ART that would prevent the infection of new targets and enrich the reservoir in cells with inactive proviruses. This scenario is the one described for PWH called Elite Controllers (EC) due to their immune system can control naturally the viral replication and so they do not need to take ART to avoid viral dissemination and transmission. In EC, the provirus appears to be in a state of deep latency that means that most or even all the cells that form part of the viral reservoir are transcriptionally silent and the provirus cannot be reactivated even if it is intact or competent. Although EC represent less than 1% of PWH, they have become very important to understand the workings of the viral reservoir and to design new therapeutic strategies that may permit all PWH to achieve this state of deep latency in the absence of ART.
The beginning of ART occurred in 1996, which means that there are now PWH who have been on ART for more than 20 years. Several studies have been conducted in these individuals to try to determine if such a long ART has significantly modified the reservoir landscape, reducing the number of cells with transcriptionally active proviruses. Due to cells containing intact proviruses located in transcriptionally active locations may be detectable by the immune system or more susceptible to die during the viral replication, theoretically the viral reservoir would get progressively enriched in cells harboring defective proviruses or intact proviruses located in silent regions of the cellular chromosomes that are unlikely being reactivated.
The effect of ART on the viral reservoir is evident since the reactivation of proviruses in PWH with chronic infection and long-term ART appears to be originated from selected cell clones with transcriptionally active proviruses. This means that the pressure exerted by the immune system and ART is continuously changing the reservoir landscape and selecting these specific clones that are maintaining the viral persistence. But how much time on ART is necessary to induce this change? And importantly, this evolution could at some point eliminate the viral reservoir?
The selection of cells from the viral reservoir with defective proviruses seems to occur at least after 20 years of ART. So, is it possible that PWH on ART for so long are now resembling EC? This question is difficult to answer due to PWH has a wide range of presentations because of the large number of factors that may be influencing the integrity of the viral reservoir. In the studies that have been performed by now, some PWH have attained a favorable scenario in which the viral reservoir has been modified by ART and intact proviruses are now undetectable. Does it mean that these individuals may discontinue ART and wait to see if there is not a viral rebound?
Likely not because most studies that have evaluated the size and composition of the viral reservoir have been performed in blood, which constitutes the most accessible fluid of our organism that contains significant quantities of cells from the viral reservoir. But the reservoir in tissues is much larger than in blood, such as in lymph nodes, gut-associated lymphoid tissue, spleen, and even in the central nervous system, which can be inaccessible for ART. Therefore, more studies are needed to determine the time on ART that would significantly modify the viral reservoir not only in blood but also in tissues to achieve a deep latency state similar to EC. These studies should be performed individually as every person with HIV is different.