The earliest events that occur following mucosal HIV-1 exposure remain poorly understood, largely because the eclipse period of infection prior to the detectable disease is very difficult to study in humans. Now, a study from researchers led by Beth Israel Deaconess Medical Center (BIDMC) reveals what happens in the very earliest stages of HIV infection, before the virus is even detectable in the blood, the most comprehensive evaluation of acute HIV/SIV infection to date. The team state that their findings have critical implications for vaccine development and other strategies to prevent infection. The opensource study is published in the journal Cell.
Previous studies show that the events during the first few days after exposure to HIV virus and prior to the initial detection of the virus in blood are critical in determining the course of infection, however, this period is essentially impossible to study in humans. The current study shows that the HIV triggers specific host mechanisms that suppress the generation of antiviral innate and adaptive immune responses in the first few days of infection, thus facilitating its own replication.
The current study observed 44 rhesus monkeys exposed to SIV, the animal equivalent of HIV, and conducted analyses of the animals on days 0, 1, 3, 7 and 10 following exposure. Results showed that SIV could disseminate rapidly through the body, with viral RNA present in at least one tissue outside the reproductive tract in most monkeys analyzed 24 hours after exposure. Data findings show that in addition to rapid viral dissemination, the virus triggered a local inflammatory response which appears to suppress antiviral innate and adaptive immunity, thus potentially augmenting its own replication. The lab state that these data provide important insights into the earliest events of infection.
Results show that the inflammatory response occurred in tissues soon after exposure to SIV, and increasing amounts of viral RNA correlated with rising amounts of a host protein called NLRX1, which inhibits antiviral immune responses. Data findings show that the TGF-beta cell-signaling pathway, which suppresses adaptive immune responses, was triggered and correlated with lower levels of antiviral T immune cell responses, as well as higher levels of SIV replication. The group observed elevated expression of genes in the TGF-beta pathway in tissues that contained viral RNA as early as day 1 after exposure to the virus.
The team surmise that their findings suggest there maybe a very narrow window of opportunity to contain or eliminate the virus and HIV prevention strategies should take these factors into account. They go on to add that they believe these insights into early HIV/SIV infection will be critical for the development of interventions to block infection, such as vaccines, antibodies, microbicides and drugs. For the future, the researchers state that the next step in this line of research is to evaluate how various interventions may impact these early events.
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