Latency describes the persistence of a microorganism within its host in the absence of clinical symptoms of disease. Both microorganism and host benefit from induction of latency: the microorganism establishes a stable environment that facilitates survival, and the host avoids progressive damage and disease. Latent states have been observed in bacterial, viral, fungal, and parasitic infectious diseases, though the mechanisms differ within each microorganism and host pair. In this issue, a Review Series on Latency in Infectious Disease explores the different strategies that various microorganisms use to achieve latency. Conceptualized by JCI’s Deputy Editor Arturo Casadevall, the series highlights the latency mechanisms employed by herpesviruses, HIV, Cryptococcus neoformans, and Toxoplasma gondii. In addition to describing mechanisms, the reviews outline the detrimental effects of latent disease and recent progress toward treatment and eradication.
Although antiretroviral therapies (ARTs) potently inhibit HIV replication, they do not eradicate the virus. HIV persists in cellular and anatomical reservoirs that show minimal decay during ART. A large number of studies conducted during the past 20 years have shown that HIV persists in a small pool of cells harboring integrated and replication-competent viral genomes. The majority of these cells do not produce viral particles and constitute what is referred to as the latent reservoir of HIV infection. Therefore, although HIV is not considered as a typical latent virus, it can establish a state of nonproductive infection under rare circumstances, particularly in memory CD4+ T cells, which represent the main barrier to HIV eradication. While it was originally thought that the pool of latently infected cells was largely composed of cells harboring transcriptionally silent genomes, recent evidence indicates that several blocks contribute to the nonproductive state of these cells. Here, we describe the virological and immunological factors that play a role in the establishment and persistence of the pool of latently infected cells and review the current approaches aimed at eliminating the latent HIV reservoir.
Caroline Dufour, Pierre Gantner, Rémi Fromentin, Nicolas Chomont
Cryptococcus neoformans is an opportunistic yeast that is present worldwide and interacts with various organisms. In humans, it is responsible for cryptococcosis, a deadly invasive fungal infection that represents around 220,000 cases per year worldwide. Starting from the natural history of the disease in humans, there is accumulating evidence on the capacity of this organism to enter dormancy. In response to the harsh host environment, the yeast is able to adapt dramatically and escape the vigilance of the host’s immune cells to survive. Indeed, the yeast exposed to the host takes on pleiotropic phenotypes, enabling the generation of populations in heterogeneous states, including dormancy, to eventually survive at low metabolic cost and revive in favorable conditions. The concept of dormancy has been validated in C. neoformans from both epidemiological and genotyping data, and more recently from the biological point of view with the characterization of dormancy through the description of viable but nonculturable cells.
Herpesviruses infect virtually all humans and establish lifelong latency and reactivate to infect other humans. Latency requires multiple functions: maintaining the herpesvirus genome in the nuclei of cells; partitioning the viral genome to daughter cells in dividing cells; avoiding recognition by the immune system by limiting protein expression; producing noncoding viral RNAs (including microRNAs) to suppress lytic gene expression or regulate cellular protein expression that could otherwise eliminate virus-infected cells; modulating the epigenetic state of the viral genome to regulate viral gene expression; and reactivating to infect other hosts. Licensed antivirals inhibit virus replication, but do not affect latency. Understanding of the mechanisms of latency is leading to novel approaches to destroy latently infected cells or inhibit reactivation from latency.
Jeffrey I. Cohen
Toxoplasma gondii is an incredibly successful parasite owing in part to its ability to persist within cells for the life of the host. Remarkably, at least 350 host species of T. gondii have been described to date, and it is estimated that 30% of the global human population is chronically infected. The importance of T. gondii in human health was made clear with the first reports of congenital toxoplasmosis in the 1940s. However, the AIDS crisis in the 1980s revealed the prevalence of chronic infection, as patients presented with reactivated chronic toxoplasmosis, underscoring the importance of an intact immune system for parasite control. In the last 40 years, there has been tremendous progress toward understanding the biology of T. gondii infection using rodent models, human cell experimental systems, and clinical data. However, there are still major holes in our understanding of T. gondii biology, including the genes controlling parasite development, the mechanisms of cell-intrinsic immunity to T. gondii in the brain and muscle, and the long-term effects of infection on host homeostasis. The need to better understand the biology of chronic infection is underscored by the recent rise in ocular disease associated with emerging haplotypes of T. gondii and our lack of effective treatments to sterilize chronic infection. This Review discusses the cell types and molecular mediators, both host and parasite, that facilitate persistent T. gondii infection. We highlight the consequences of chronic infection for tissue-specific pathology and identify open questions in this area of host-Toxoplasma interactions.
Xiao-Yu Zhao, Sarah E. Ewald
The state of latency occurs when a microbe’s persistence in a host produces host damage without perturbing homeostasis sufficiently to cause clinical symptoms or disease. The mechanisms contributing to latency are diverse and depend on the nature of both the microbe and the host. Latency has advantages for both host and microbe. The host avoids progressive damage caused by interaction with the microbe that may translate into disease, and the microbe secures a stable niche in which to survive. Latency is clinically important because some latent microbes can be transmitted to other hosts, and it is associated with a risk for recrudescent microbial growth and development of disease. In addition, it can predispose the host to other diseases, such as malignancies. Hence, latency is a temporally unstable state with an eventual outcome that mainly depends on host immunity. Latency is an integral part of the pathogenic strategies of microbes that require human (and/or mammalian) hosts, including herpesviruses, retroviruses, Mycobacterium tuberculosis, and Toxoplasma gondii. However, latency is also an outcome of infection with environmental organisms such as Cryptococcus neoformans, which require no host in their replicative cycles. For most microbes that achieve latency, there is a need for a better understanding and more investigation of host and microbial mechanisms that result in this state.
Liise-anne Pirofski, Arturo Casadevall