Experimental Combination Surprises with Anti-HIV Effectiveness

January 20, 2016 • Science Update

A compound developed to protect the nervous system from HIV surprised researchers by augmenting the effectiveness of an investigational antiretroviral drug beyond anything expected. The potency of the combination treatment, tested so far in mice, suggests that it would be possible to rid the body of HIV for months, reducing the frequency with which patients must take these medications from daily to several times a year.

Even when people with HIV infection take antiretroviral drugs, more than 50 percent have HIV-associated neurocognitive disorders (HAND), which can result in any of a variety of symptoms, including confusion and problems with memory. NIH-supported scientists led by Harris A. Gelbard, M.D., Ph.D., at the University of Rochester School of Medicine and Dentistry developed the compound URMC-099 to protect against HIV-associated neurologic damage. This and similar compounds would always be administered with an antiretroviral medication; the objective of this research was to test URMC-099 as such an adjunct.

The antiretroviral medication used is in a class of anti-retroviral drugs (protease inhibitors) commonly used to treat HIV, but in this case, NIH-supported researchers at the University of Nebraska Medical Center, led by Howard E. Gendelman, M.D., used nanotechnology to reconstitute the compound in an effort to enhance its ability to reach and remain in target tissues. (Nanotechnology involves use or creation of materials in very small dimensions—billionths of a meter.) The process renders the drug into crystal form and adds a protective coat. The small scale formulation of nano-antiretroviral therapy (nanoART) enables it to penetrate and endure in immune cells, forming reservoirs of antiretroviral activity.

Previous work had shown that URMC-099 was anti-inflammatory and protected neuronal tissue. Used alone it is not antiviral, but it was possible, the researchers reasoned, that its anti-inflammatory effects could enhance the beneficial effects of an antiviral. They tested the combination therapy in HIV-infected mice that have what is essentially a human immune system; human immune stem cells are introduced in mice that are born lacking components of a normal immune system. On a number of measures, URMC-099 enhanced the effects of nanoART beyond expectations. It reduced HIV levels beyond what nanoART could achieve alone and below what is detectable. It increased the ability of nanoART to form persistent antiretroviral “depots” in immune cells which are thought to be central to these drugs’ ability to inhibit HIV replication.

“Our ultimate hope is that we’re able to create a therapy that could be given less frequently than the daily therapy that is required today,” said Gelbard. “If a drug could be given once every six months or longer, that would greatly increase compliance, reduce side effects, and help people manage the disease, because they won’t have to think about taking medication every day.”

“The NIH Office of AIDS Research has identified the development of long acting HIV therapies and research towards a cure as high priority topics for research support,” said Dianne M. Rausch, Ph.D., director of NIMH’s Division of AIDS Research. “The nanoformulation strategies reported here could facilitate targeting HIV anatomic reservoirs such as lymph nodes and brain which are currently difficult to reach because of limited penetration of anti-retroviral drugs into tissue compartments.”

This work was supported by the National Institute of Mental Health along with the National Institute of Allergy and Infectious Diseases, the National Institute on Drug Abuse, the National Institute of Neurological Disorders and Stroke, and the National Institute on Aging. It appears in the January 2016 issue of the journal Nanomedicine.

Grants

MH64570, MH104147, AI078494, DA028555, NS36126, NS31492, NS034239, NS43985, MH062261, AG043540

Reference

Zhang G, Guo D, Dash PK, Arainga M, Wiederin JL, Haverland NA, Knibbe-Hollinger J, Martinez-Skinner A, Ciborowski P, Goodfellow VS, Wysocki TA, Wysocki BJ, Poluektova LY, Liu XM, McMillan JM, Gorantla S, Gelbard HA, Gendelman HE. The mixed lineage kinase-3 inhibitor URMC-099 improves therapeutic outcomes for long-acting antiretroviral therapy. Nanomedicine. 2015 Oct 22. pii: S1549-9634(15)00187-2. doi: 10.1016/j.nano.2015.09.009.