It’s not better latent than never: common infections may allow HIV to persist
Human immunodeficiency virus (HIV) remains a substantial global health burden. In 2018 (most recent statistic), around 2 million new HIV infections were reported worldwide. The virus infects an important cell of the immune system known as a CD4+ T cell. These cells express a protein on their membrane surface called CD4 (hence their name) which the virus co-opts to enter the T cell. Along with two other surface proteins, CCR5 or CXCR4, HIV attaches to the T cell and proceeds inside to use the T cell’s own machinery to replicate itself. Over time, this kills CD4+ T cells and, because CD4+ T cells are required to protect an individual from other infections, HIV-infected individuals develop acquired immunodeficiency syndrome (AIDS) and can die from even minor infections that the immune system would normally clear.
HIV integrates its own genetic material into the DNA of the infected individual. While this is required to produce more copies of the virus, sometimes CD4+ T cells can become infected without reproducing the virus. This is called a latent HIV reservoir and is a major barrier to curing HIV infection because it allows the virus to hide and persist for a long time.
A hallmark of any immune response is the activation of CD4+ T cells leading them to make many copies of themselves so as to fight the infection. This raises a very interesting question – when a HIV+ patient must fight a different infection, for example the flu, does the expansion of CD4+ T cells harbouring HIV contribute to HIV’s longevity? The answer is yes, and this seems like a cruel twist of the HIV life cycle. This was the focus of the work led by Dr. Lillian Cohn and Dr. Michel Nussenzweig.
These scientists tested this by isolating CD4+ T cells from the blood of HIV-infected individuals. They then stimulated the T cells with a variety of proteins (also called antigens) from common viruses or bacteria and assessed whether, among the activated cells, HIV could be detected. Indeed, competent proviral sequences could be detected – that is, genetic elements that encode the ability for HIV to replicate were found. This led the researchers to conclude that common infections could lead activated but HIV-infected T cells to perpetuate the genetic material of HIV.
Understanding how latent reservoirs persist is important for developing effective therapies that eradicate HIV infection. While there are effective drug treatments that suppress HIV, there is no known cure. One key question that remains is how and why latently infected cells are able to divide extensively and rapidly without succumbing to reactivation of HIV. It is possible that other genes are expressed that prevent or suppress viral DNA from being copied. Alternatively, the viral DNA integrated into a region of the genome that is inactive and therefore cannot be copied.
This study provides a meaningful contribution to our understanding of HIV latency. Dr Cohn is continuing to follow up this work as a fellow at the Chan Zuckerberg Biohub and the University of California San Francisco. “Our work is now focused on understanding whether HIV-1 infected, antigen-specific cells contribute to rebound viremia during treatment interruption” she said. They are particularly interested in whether chronic viral antigens are the main drivers of the latent reservoir rather than transient infections like influenza. Dr Cohn also thinks the work could be extended to infections like SARS-CoV-2, the causative virus of COVID-19. “We’re currently partnering with clinicians at UCSF to obtain samples from COVID-19 survivors who are also HIV-positive to see whether SARS-CoV-2 specific T cells can harbor HIV proviruses”.
By Jeremy Brooks
See primary article at https://rupress.org/jem/article/217/7/e20200051/151689/Antigen-responsive-CD4-T-cell-clones-contribute-to?searchresult=1
Schema describing the molecular events of HIV infection, reproduced from the NIAID-NIH website.
https://www.niaid.nih.gov/diseases-conditions/hiv-replication-cycle