"To date, HIV infection has only been cured in a very small number of highly-publicized but unusual clinical cases in which HIV-infected individuals were treated with anti-viral medicines very early after the onset of infection or received a stem cell transplant to combat cancer,” said Louis Picker, M.D., associate director of the OHSU Vaccine and Gene Therapy Institute. “This latest research suggests that certain immune responses elicited by a new vaccine may also have the ability to completely remove HIV from the body.”
Nature - Immune clearance of highly pathogenic SIV infection
The Picker lab's approach involves the use of cytomegalovirus, or CMV, a common virus already carried by a large percentage of the population. In short, the researchers discovered that pairing CMV with SIV had a unique effect. They found that a modified version of CMV engineered to express SIV proteins generates and indefinitely maintains so-called "effector memory" T-cells that are capable of searching out and destroying SIV-infected cells.
T-cells are a key component of the body's immune system, which fights off disease, but T-cells elicited by conventional vaccines of SIV itself are not able to eliminate the virus. The SIV-specific T-cells elicited by the modified CMV were different. About 50 percent of monkeys given highly pathogenic SIV after being vaccinated with this vaccine became infected with SIV but over time eliminated all trace of SIV from the body. In effect, the hunters of the body were provided with a much better targeting system and better weapons to help them find and destroy an elusive enemy.
“Through this method we were able to teach the monkey's body to better 'prepare its defenses' to combat the disease," explained Picker. “Our vaccine mobilized a T-cell response that was able to overtake the SIV invaders in 50 percent of the cases treated. Moreover, in those cases with a positive response, our testing suggests SIV was banished from the host. We are hopeful that pairing our modified CMV vector with HIV will lead to a similar result in humans.”
The Picker lab is now investigating the possible reasons why only a subset of the animals treated had a positive response in hopes that the effectiveness of the vaccine candidate can be further boosted.
Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 . Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69–172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.
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