EXECUTIVE SUMMARY

In two separate papers, scientists have documented how their efforts reversed HIV and simian immunodeficiency virus latency in two animal models. Findings indicated progress toward an HIV cure.

• Investigators from the Collaboratory of AIDS Researchers for Eradication conducted the new research, funded by the National Institutes of Health.

• Research efforts identified a compound called AZD5582, which belongs to a class of molecules that have proven safe as experimental cancer therapeutics.


In two separate papers, scientists have documented how their efforts reversed HIV and simian immunodeficiency virus (SIV) latency in two animal models. Findings indicated progress toward an HIV cure.1,2

The research was conducted by investigators at the Collaboratory of AIDS Researchers for Eradication, based at the University of North Carolina at Chapel Hill and the Emory Consortium for Innovative AIDS Research in Nonhuman Primates. Both efforts were funded by the National Institutes of Health (NIH).

“A simple, safe, and scalable cure for HIV is an aspirational goal that, if achieved, would accelerate progress toward ending the HIV pandemic,” Anthony Fauci, MD, director of the NIH’s National Institute of Allergy and Infectious Diseases, said in a statement. “These new findings help sustain our cautious optimism that an HIV cure is possible.”3

Scientists reactivated resting immune cells that were latently infected with HIV or SIV in cells in the bloodstream and a variety of animal tissues. The reactivated cells made copies of the virus, which could be neutralized by anti-HIV drugs and the immune system.1,2

New Compounds Under the Microscope

The persistence of viral reservoirs, where the HIV virus hides from the immune system, has made developing an HIV cure extremely difficult. These reservoirs consist of HIV-infected cells that contain genetic material capable of generating new virus particles if treatment is interrupted. These affected cells enter a resting state until activated to produce the virus. When the cells are resting, the immune system cannot recognize and kill them, rendering antiretroviral therapy ineffective.

Activating HIV reservoirs so therapeutic agents or an enhanced immune system can recognize and kill the infected cells has proven tricky. While laboratory efforts have worked well, testing in animal and human models have resulted in ineffective or toxic results.

Research efforts identified a compound called AZD5582, which belongs to a class of molecules that have been proven safe as experimental cancer therapies. In one experiment, researchers used 20 mice with human immune systems, infected them with HIV, and administered antiretroviral therapy to suppress the virus. Ten mice were injected with AZD5582, and the other 10 received placebo.

High levels of HIV RNA were detected in the blood of six of the AZD5582-treated mice within 48 hours, researchers reported. Scientists confirmed that the compound activated resting cells in the HIV reservoir throughout the treated mice without causing toxicity or immune system activation.2

Researchers also worked with 21 rhesus macaques, infecting them with SIV and providing suppressive antiretroviral therapy. More than a year after the therapy initiation, scientists administered weekly intravenous infusions of AZD5582 to 12 monkeys for either three or 10 weeks. Data suggested that the level of SIV increased in the blood of five of the nine monkeys (55%) that received 10 doses of AZD5582, and in none of the three monkeys that received fewer doses. Researchers reported that SIV RNA levels in resting immune cells from the monkeys’ lymph nodes registered higher in animals treated with 10 doses of AZD5582 than in the nine monkeys that did not receive the compound.2

“It will be important to test other compounds in the same class of AZD5582 and possibly in combination with other latency reversal agents to determine which might be the best for testing in humans,” says Victor Garcia, PhD, director of the International Center for the Advancement of Translational Science, professor of medicine and microbiology and immunology at the University of North Carolina at Chapel Hill School of Medicine. “If the results of these follow-up studies are successful, an early clinical trial may follow.”

The authors of a different paper detailed how a combination of two agents affected the SIV reservoir in rhesus macaques and the HIV reservoir in mice with human immune systems when both animal models received antiretroviral therapy. The combination included an antibody, MT807R1, which depletes immune cells known as CD8+ T cells, and N-803, an engineered protein complex that activates certain immune cells to fight pathogens.

Scientists first infected 35 rhesus macaques with SIV and administered antiretroviral therapy, which suppressed the virus in 33 of the animals. Following at least one year after therapy initiation, researchers gave seven monkeys N-803, 14 monkeys MT807R1, and 14 monkeys the compound.

While N-803 alone had no effect on the SIV reservoir, data suggested MT807R1 alone led to a moderate increase in the level of SIV in the viral load. However, the combination of MT807R1 and N-803 led to a robust and persistent increase in the SIV viral load of all 14 animals, including the six in which fewer than three copies of SIV were detected before the experimental treatment began.1

“The exciting thing about these papers being published together are the concordance of the results in two animal models with both approaches, and the opening up of new avenues for research toward the goal of an HIV cure,” Ann Chahroudi, MD, PhD, associate professor of pediatrics and director of the Center for Childhood Infections and Vaccines at Emory and Children’s Healthcare of Atlanta.4

REFERENCES

  1. McBrien JB, Mavigner M, Franchitti L, et al. Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells. Nature 2020;578:154-159.
  2. Nixon CC, Mavigner M, Sampey GC, et al. Systemic HIV and SIV latency reversal via non-canonical NF-kB signalling in vivo. Nature 2020;578:160-165.
  3. National Institute of Allergy and Infectious Diseases. NIH-supported scientists reverse HIV and SIV latency in two animal models, Jan. 22, 2020. Available at: https://bit.ly/2Hjt3dW.
  4. Woodruff Health Sciences. In animal models, a ‘shocking’ step toward a potential HIV cure, Jan. 22, 2020. Available at: https://bit.ly/2SJwsbc.