www.hivandhepatitis.com

Broadly Neutralizing Antibodies May Prevent Reservoir HIV from Entering T-Cells

HIV-specific broadly neutralizing antibodies may be able to prevent virus emerging from latent reservoir sites from entering CD4 T-cells, as well as suppressing viral replication if HIV does manage to get in, according to NIAID research published in the August 25 advance edition of Proceedings of the National Academy of Sciences.

Soon after infection HIV establishes a reservoir of viral genetic material in resting T-cells and perhaps elsewhere in the body. This latent virus is hidden from the immune system and not susceptible to antiretroviral drugs. If antiretroviral therapy (ART) is discontinued, this hidden virus can wake up and begin replicating, which makes HIV very difficult to eradicate.

Researchers are studying several approaches towards a cure for HIV, including strategies that awaken latent HIV in resting T-cells, protect new cells from viral entry, and strengthen the immune system's own responses against the virus.

Tae-Wook Chun and Anthony Fauci from the National Institutes of Allergy and Infectious Diseases and colleagues evaluated the activity of broadly neutralizing antibodies -- meaning they can recognize and respond to multiple strains of HIV -- against virus obtained from 29 individuals on long-term suppressive ART.

While broadly neutralizing antibodies have been isolated from B-cells of HIV-infected people, and such antibodies have been shown to prevent the virus from entering cells in laboratory and animal studies, their effectiveness against HIV in humans -- and especially against the latent viral reservoir -- is unknown.

The researchers identified several broadly neutralizing monoclonal antibodies -- in particular PGT121, VRC01, and VRC03 -- that blocked HIV isolated from the latent reservoir of infected people on suppressive ART from entering CD4 T-cells obtained from both HIV positive and HIV negative people. In addition, they found that these same antibodies also strongly suppressed viral replication in autologous (from the same individual) T-cells of HIV-infected people.

These findings suggest that passive immunotherapy using injected antibodies may help control HIV rebound after stopping ART. Clinical trials are currently underway or being planned to test this approach. Most experts expect that a combination approach will be needed to produce a "functional cure" that could allow people with HIV to remain off ART for extended periods without disease progression, and HIV-specific antibodies broadly neutralizing may be one component.

"Our findings have potentially important implications for the design of therapeutic strategies," they wrote. "A combination of HIV-neutralizing monoclonal antibodies, particularly PGT121, VRC01, and VRC03, may provide sustained virologic remission in infected individuals following the discontinuation of ART."

"The above approach is a realistic therapeutic strategy given the potent activities of these antibodies against HIV isolated from the persistent viral reservoir and their likely long-circulating half-lives," they continued. "With the possibility of biochemical modification allowing for a more prolonged plasma half-life, it is conceivable that HIV-infected individuals could potentially maintain very low or undetectable plasma viremia in the absence of ART following relatively infrequent administration of these antibodies."

8/28/14

Reference

T-W Chun, D Murray, J Justement, A Fauci, et al.Broadly neutralizing antibodies suppress HIV in the persistent viral reservoir. Proceedings of the National Academy of Sciences-USA. August 25, 2014 (Epub ahead of print).

Other Source

National Institutes of Allergy and Infectious Diseases. HIV Antibodies Block Infection by Reservoir-Derived Virus in Laboratory Study. NIH News press release. August 26, 2014.