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Researchers Observe Sustained Remission in Monkeys with HIV-Like Virus

Researchers have induced sustained remission of simian immune deficiency virus (SIV), a relative of HIV, in macaque monkeys treated with antiretroviral therapy (ART) and an antibody-based therapy used to treat inflammatory bowel disease, according to a report in the October 14 edition of Science. The monkeys not only had undetectable viral load for up to nearly 2 years after stopping treatment, but they also showed replenishment of key immune cells in the gut.

"The new findings suggest an alternative form of HIV therapy that may eliminate a requirement for lifelong daily ART, potentially improving the quality of life for people living with the virus and reducing the staggering, unmet cost of antiretroviral therapy for the 37 million people worldwide who need it," senior investigator Aftab Ansari from Emory University School of Medicine said in a National Institutes of Allergy and Infectious Diseases (NIAID) press release.

Soon after infection, SIV and HIV establish reservoirs in longed-lived CD4 T-cells, where viral genetic material can remain in an inactive state indefinitely. Antiretroviral treatment keeps viral replication in check, but once the drugs are interrupted the virus almost always reactivates and resumes its assault on immune cells, so people with HIV must remain on ART for life.

Scientists have explored a number of methods for curing HIV -- or, more likely, enabling long-term remission after stopping treatment -- including very early ART, latency-reversing agents that "wake up" inactive virus, stem cell transplants, and gene therapy, but so far this research has not produced a broadly applicable strategy. Most experts believe a combination approach will be needed.

Ansari, Anthony Fauci from NIAID, andcolleagues explored one such approach in a non-human primate study, using ART plus a "primatized" monoclonal antibody against α₄β₇ integrin. Integrins are receptors that play a role in cellular adhesion and inflammation. The α4ß7 integrin on CD4 T-cells helps these cells migrate to gut tissue -- one of the first sites where reservoirs are established in early SIV or HIV infection -- and facilitates cell infection. The experimental antibody preparation is similar to the human drug vedolizumab (Entyvio), which is approved for treatment of ulcerative colitis and Crohn’s disease.

The researchers started 18 rhesus macaque monkeys on ART at 5 weeks after SIV infection, which was continued for 90 days. At 9 weeks, 11 of the monkeys also began receiving infusions of the experimental antibody administered every 3 weeks until week 32, while the other 7 got placebo antibody infusions. All treatment was halted at 32 weeks.

Results

• All monkeys achieved full SIV suppression by the third week on ART.
• 3 animals treated with the integrin antibody developed antibodies against the therapy and were excluded from further analysis.
• Of the remaining 8 monkeys that received the integrin antibody, 2 maintained consistent viral suppression after stopping ART, while the other 6 experienced temporary viral rebound followed by re-suppression.
• SIV in blood and gut tissue has remained suppressed in the 8 treated monkeys for more than 9 months -- and as long as 23 months -- since the end of treatment, according to NIAID.
• In contrast, all 7 monkeys that received placebo infusions experienced SIV rebound to a high level within 2 weeks, and viral load remained high.
• The monkeys treated with the integrin antibody also regained normal CD4 T-cell counts in their blood and replenishment of uninfected CD4 cells in their gut tissue.

"This combination therapy allows macaques to effectively control viremia and reconstitute their immune systems without a need for further therapy," the study authors concluded.

Experts expressed surprise at the findings, while emphasizing that the monkeys cannot be said to be cured at this point. Researchers do not know how the integrin antibody works to keep viral replication in check, but Ansari suggested that understanding this could aid in developing an effective HIV vaccine.

"Our data suggest that the immune systems of these animals are controlling SIV replication in the absence of antiretroviral therapy," said Fauci. "The experimental treatment regimen appears to have given the immune systems of the monkeys the necessary boost to put the virus into sustained remission."

"The precise mechanisms of this effect are unclear and will be actively pursued since they could have important implications for the control of HIV infection in humans in the absence of ART," he continued. "At this point it is also unclear whether the findings of the newly reported animal study will translate into a clinical benefit for HIV-infected people."

To investigate this possibility, researchers are now conducting an early-phase clinical trial of ART plus short-term vedolizumab for 20 people with chronic HIV infection (NCT02788175), which plans to include an analytical treatment interruption. Preliminary results are expected by the end of 2017, according to NIAID.

10/16/16

Sources 

SN Byrareddy, J Arthos, C Cicala, et al. Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy. Science 354(6309):197-202. October 14, 2016.

National Institutes of Health. Scientists at NIH and Emory Achieve Sustained SIV Remission in Monkeys. Press release. October 13, 2016.

J Cohen. Antibody treatment surprisingly 'cures' monkeys of HIV-like infection. Science. October 13, 2016.