First-ever study captures HIV cell-to-cell transmission in a living animal.


HIV, is a virus that attacks the body’s immune system. If left untreated, HIV can progress and develop into AIDS.  HIV infection is enhanced by adhesive structures that form between infected and uninfected T cells called virological synapses. This mode of transmission results in the frequent co-transmission of multiple copies of HIV across the virological synapses, which can reduce sensitivity to antiretroviral drugs.  However, the extent of virological synapse-mediated spread that occurs in the body is still unclear.  Now, a study from researchers at the Icahn School of Medicine at Mount Sinai shows how infected immune cells latch onto an uninfected sister cell to directly transmit viral particles by watching brightly glowing HIV-infected immune cells move within mice. The team state that these interactions allow HIV to spread efficiently between these immune cells, known as CD4+ helper T cells, challenging the long-held perception that the primary route of HIV infection of immune cells is from free-floating viral particles that move within tissue and blood fluids.  The opensource study is published in the journal Cell Reports.

Previous studies in cell culture have indicated that cell-to-cell infection may help HIV to resist antibodies and potent therapies, with all HIV treatment to date has based on the free-floating virion model.  Therefore, it is critical to study cell-to-cell infection and how multicopy infection operates in vivo to better understand how HIV persists during antiretroviral therapy and evades neutralizing responses. The current study uses live imaging to examine how infected and uninfected CD4+ T cell interactions contribute to the formation of segregated clusters of viral replication.

The current study attached green fluorescent molecules derived from jellyfish and red glowing proteins from coral onto variants of HIV. Two strains were introduced into mice transplanted with a human immune system and watched in real time as HIV spread from one CD4+ helper T cell to another.  Results show that hot spots of infection could be visualised within lymphoid tissue, which has millions of cells moving dynamically within the tissue.  Data findings show that by focusing just on the green and red glowing cells, infected cell influences on uninfected cells could be monitored.

Results show that using an advanced imaging technique called intravital microscopy, the movement and interaction of HIV-infected cells in the spleen of mice could be observed. The team watched as infected cells induced contact with uninfected cells, and the uninfected cell would then pause for a time on the infected cell, building a physical connection between them.  The lab explain that these infectious connections are known as virological synapses because they resemble the way that cells of the nervous system or the immune system communicate through intimate cell-to-cell connections.

The group hypothesize the proteins that make up the HIV virion are being assembled at the site of the virological synapse bridge and then directly moved to the cell being infected. They go on to add that cell-to-cell infection allows several viruses to simultaneously pass between the connected cells. The researchers found that multiple viruses could infect a single cell through virological synapses.

Results show that this pathway allows multiple copies of HIV to transmit together from cell-to-cell, a genetic property that can help mutant viruses to accumulate. The lab state that this may help explain the high mutation rate that allows the virus to escape from immune responses; the genetic-mixing that happens when a cell is infected with multiple HIV virions can lead to novel genetic recombination that then gets passed into the next immune cell that is infected.

The team surmise that while HIV cell-to-cell transmission has been observed in test tube experiments, this is the first study to capture these interactions in a living animal. They go on to add that although cell-to-cell infection does result in release of abundant solo viral particles, direct transmission from HIV-infected immune cells to other cells, which can then replicate in clusters of these cells, is a much more efficient route to quickly spread the virus. For the future, the researchers state that their findings could mean HIV cell-to-cell transmission maybe particularly important in allowing the virus to spread in the body even before it is detectable in the blood.

Source: Mount Sinai Hospital

 

Credit: Thomas Deerinck, NCMIR/SPL.

Credit: Thomas Deerinck, NCMIR/SPL.

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