By Shivani Rajhansa
The human immunodeficiency virus (HIV) epidemic became rampant in the mid-late 1970s (History of HIV and AIDS overview, 2019) and almost 33 million people have died since then (HIV/AIDS, 2020). HIV acts by destroying CD4+ T lymphocytes which weakens the immune system and makes it difficult for the body to fight infections and certain cancers. The virus is transmitted through bodily fluids such as blood, semen, vaginal fluids, rectal fluids, and breast milk. Once in the body, it slowly destroys the immune system and the infection eventually reaches its most advanced stage: acquired immunodeficiency syndrome (HIV/AIDS: The Basics, 2019). HIV used to be a death sentence, but the increasing availability of treatment means that more people are able to live long, healthy lives (HIV/AIDS, 2020).
Antiretroviral therapy (ART) is recommended for anyone with HIV. ART is a combination of medicines that are taken every day to reduce the body’s viral load by preventing HIV from multiplying. Limiting the viral load enables the immune system to recover and remain strong enough to stop advancement to AIDS. ART keeps the viral load at an undetectable level which also prevents further transmission (HIV Treatment: The Basics, 2020). However, ART does not eliminate HIV from one’s body; it is not a cure. The treatment must be continued for an individual’s entire life and any interruptions in the treatment can lead to a rebound in viral load. Recent research in the field has given us insight into how a functional cure could be achieved.
The answer to this issue might lie in a group of people that make up around 0.5% of the HIV-infected population. Called the “elite controllers”, this group has the ability to control HIV replication and maintain viral load below detectable levels without needing any medication (Jiang et al., 2020). This ability has been linked with certain mutations in the human HLA class I gene locus (McLaren and Carrington, 2015), and powerful “immune responses that have stronger abilities to kill virus-infected cells, target mutationally constrained epitopes and limit viral escape” (Jiang et al., 2020). There is a small but enduring pool of replication-competent proviruses in elite controllers, but the differentiating factors and overall characteristics of the reservoir cells of these individuals were only recently examined.
What exactly is it about elite controllers that allows them to “defeat” HIV without any treatment? To find the answer to this Jiang et al. compared the viral reservoirs of elite controllers with those of individuals who are prescribed with ART. First, full-length individual provirus sequencing was used to analyse a large amount of individual proviral genomes from both groups. As expected, they found fewer copies of the HIV-1 genome, both intact and defective, in the elite controller group. Interestingly however, a larger percentage of the copies in elite controllers were genetically intact. Genetically intact copies are able to be transcribed into infectious viruses. Furthermore, copies of the viral genome in elite controllers were identical. These observations implied that the proviruses in elite controllers do have the ability to proliferate and produce viral particles. As mentioned earlier, this group of people is known to induce potent immune responses against virus-infected cells. How is it then, that these proviruses continue to exist in the individual over many years and are not targeted by the immune response?
This question led Jiang et al. to the most significant findings of this study. Matched integration site and proviral sequencing was used to analyse the chromosomal position and integration sites of proviral sequences in elite controllers. Comparing the two groups suggested that the proviruses in elite controllers are in a deeper state of latency than proviruses in ART-treated individuals. The HIV-1 genome was found to be integrated in intronic (non-coding) regions of the elite controller genome, consisting of dense heterochromatin ‘gene deserts’. These regions are normally not favoured for HIV-1 integration. Localisation was often in centromeric DNA which is known to be densely packaged, therefore repressing transcription. A total of 32.6% of all analysed proviral sequences from elite controllers were integrated in or close to satellite DNA such as centromeres. A large number of HIV genomes were also integrated in genes coding members of the zinc-finger protein family. This area of chromatin is also transcriptionally repressed because of molecular modifications. Furthermore, data suggested that the preferential sites for provirus integration in elite controllers include chromosomal regions that are more susceptible to DNA methyltransferases. Hypermethylation is an epigenetic modification linked with decrease in gene expression. Proviral integration into hypermethylated, transcriptionally repressed and non-coding regions of the human genome is what facilitates this deep latency of HIV observed in elite controllers, protects the few existing proviral copies from the immune response and leads to a decrease in production of viral transcripts and proteins.
There are two possible explanations for this phenomenon. One is that HIV preferentially integrates into these particular regions in elite controller genomes. The other explanation is that cells in which proviruses are integrated into these regions are selected over time while those that allow viral transcription are eliminated (Chomont, 2020). The second scenario is more likely because when Jiang et al. infected the cells of elite controllers and ART-treated individuals with HIV-1 in vitro, they showed essentially the same integration patterns (Jiang et al., 2020). The potent immune responses in elite controllers may be responsible for gradually eliminating cells containing proviruses that are able to be transcribed. Over many years this leads to a small population of provirus-containing cells that are unable to be reactivated (Chomont, 2020).
Although elite controllers only make up 0.5% of the HIV-1 infected population, this research may have positive implications for the rest of the population. Firstly, it suggests that when measuring the size of an individual’s HIV reservoir capable of viral rebound, the intactness and activation potential of the proviruses should be evaluated. Current assays only measure the number of intact viral genomes which is an inaccurate prediction of viral rebound during ART interruption as many of these genomes may be deeply latent (Chomont, 2020). Furthermore, this study implies that immune pressure on infected cells over years might significantly reduce the HIV reservoir size over time by eliminating transcriptionally active HIV genomes. This suggests that immune cell therapies (such as CAR T-cell therapies) may be useful not only in controlling viral rebound in ART interruption but also shrinking the reservoir to a small number of transcriptionally repressed and dormant proviruses (Chomont, 2020). The potential of this research to aid the development of a functional cure may be unclear; However, it has contributed further understanding into a disease that continues to be a major public health issue.
References:
AIDS Info. 2019. HIV/AIDS: The Basics. [online] Available at: <https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/19/45/hiv-aids–the-basics> [Accessed 9 September 2020].
AIDS Info. 2020. HIV Treatment: The Basics. [online] Available at: <https://aidsinfo.nih.gov/understanding-hiv-aids/fact-sheets/21/51/hiv-treatment–the-basics#:~:text=treatment%20for%20HIV%3F-,The%20treatment%20for%20HIV%20is%20called%20antiretroviral%20therapy%20(ART).,HIV%20live%20longer%2C%20healthier%20lives.> [Accessed 9 September 2020].
Avert. 2019. History Of HIV And AIDS Overview. [online] Available at: <https://www.avert.org/professionals/history-hiv-aids/overview#:~:text=It%20is%20widely%20believed%20that.> [Accessed 9 September 2020].
Chomont, N., 2020. HIV enters deep sleep in people who naturally control the virus. Nature, 585(7824).
Jiang, C., Lian, X., Gao, C., Sun, X., Einkauf, K., Chevalier, J., Chen, S., Hua, S., Rhee, B., Chang, K., Blackmer, J., Osborn, M., Peluso, M., Hoh, R., Somsouk, M., Milush, J., Bertagnolli, L., Sweet, S., Varriale, J., Burbelo, P., Chun, T., Laird, G., Serrao, E., Engelman, A., Carrington, M., Siliciano, R., Siliciano, J., Deeks, S., Walker, B., Lichterfeld, M. and Yu, X., 2020. Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Nature,.
McLaren, P. and Carrington, M., 2015. The impact of host genetic variation on infection with HIV-1. Nature Immunology, 16(6), pp.577-583.
World Health Organisation. 2020. HIV/AIDS. [online] Available at: <https://www.who.int/news-room/fact-sheets/detail/hiv-aids> [Accessed 9 September 2020].
Imperial Bioscience Review 