New technology lights up location of first cells to be infected in female HIV transmission.


The human immunodeficiency virus (HIV) is a lentivirus which causes HIV infection and over time AIDS. Developing effective prevention measures for HIV is hindered by incomplete knowledge of the phenotype and localization of the initial target cells of infection after mucosal viral exposure.  With the vulnerable points of HIV entry in the female reproductive tract likened to searching for needles in a haystack, the difficulty in detecting infected cells immediately after mucosal HIV transmission hinders understanding of the initial cells targeted by the virus. Now, researchers from Northwestern Medicine have solved that challenge by creating a glowing map of the very first cells to be infected with a HIV-like virus, namely simian immunodeficiency virus (SIV).  The team state that through an animal model they show, for the first time, that HIV enters cells throughout the entire female reproductive tract from the labia to the ovary, not just the cervix, as previously thought.  The opensource study is published in the journal Cell Host & Microbe.

Previous studies examining the earliest events after vaginal transmission have been limited by their inability to reliably detect rare infected cells using general surveys of exposed tissues. Therefore, the earliest targets of SIV/HIV mucosal transmission remain an area of debate. Earlier studies from the lab used a SIV-based dual reporter vector (LICh) to systematically identify and study small foci of events in situ 48 hr after initial infection.  The current study uses the LICh approach to routinely identify infected cells and their fates in the female reproductive tract 48 hr after vaginal SIV challenge.

The current study removed the guts from the virus and inserted a gene from lightning bugs and another gene from a fluorescent protein to generate a reporter virus; the reporter virus was then mixed with the real HIV-like virus. Results show that the glowing cells infected by the reporter revealed the site of infection with the real virus. Data findings show that after being transmitted to the host, the real virus appeared in clusters of about 20 to 30 infected cells within 48 hours.

The group state that without their new technology, they would have to take a million little sections to see if they found evidence of the virus.  Results show that the primary target of transmission is the Th17 cell, an important population of T cells in the first line of immune defense. The team note that it was previously known that they are depleted early in HIV and SIV infections.  Data findings show that within 48 hours of SIV infection there was evidence of the battle between the virus and the Th17 cell.  The researchers conclude that their data will help the global medical community design a more effective vaccine to protect women from HIV.

The team surmise that their findings suggest any strategies to efficiently prevent HIV acquisition in women likely needs to protect the entire female reproductive tract.  For the future, the researchers state to prevent women from getting infected, the very first cells must be stopped from getting infected.  They go on to add that a week after the initial infection, there are hundreds of thousands of infected cells, and it’s very difficult to stop; therefore, if the infection can be stopped earlier, there is a chance for better outcomes.

Source: Northwestern University Feinberg School of Medicine

 

The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque simian immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hr after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV-infected cells expressed the transcriptional regulator RORγt, confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17-lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission. Th17 Cells Are Preferentially Infected Very Early after Vaginal Transmission of SIV in Macaques. Hope et al 2016.

The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque simian immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hr after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV-infected cells expressed the transcriptional regulator RORγt, confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17-lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission. Th17 Cells Are Preferentially Infected Very Early after Vaginal Transmission of SIV in Macaques. Hope et al 2016.

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