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HIV Research at Johns Hopkins Institute of Basic Biomedical Sciences

HIV budding HIV escapes a cell. Source: Carl Henderson from NIAID, Wikimedia

Researchers here at the IBBS are studying the human immunodeficiency virus (HIV), how the virus releases itself from infected cells to spread and how it damages the body. HIV is spread through contact with contaminated body fluids, most often via unprotected sex or sharing needles. HIV weakens the immune system by killing infection-fighting white blood cells. If left untreated, HIV infection can lead to full-blown AIDS (acquired immunodeficiency syndrome), which causes people to be far more susceptible than uninfected people to other illnesses. IBBS researchers hope their work will someday lead to better treatments for HIV infection and AIDS.

Cell biologist and biochemist Stephen Gould  explores the formation of HIV particles—whole virus copies including the genetic material, proteins and a protective outer coating. HIV particles form as HIV escapes from one cell and infects others. Gould has evidence that the virus exits cells by exploiting the cell’s machinery normally used to package genetic material, proteins and small molecules into exosomes—small parcels released outside the cell; HIV infiltrates these little packages. By learning how cells normally make exosomes, Gould is advancing our understanding of how HIV-infected cells make HIV particles. His work has already led to identification of new targets for anti-HIV therapy.

Treatments for HIV infection have improved since the 1980s, when HIV was first identified, and when infection meant a shorter lifespan and many medical complications. Today patients are treated with highly active antiretroviral therapy (HAART), which stops the virus from replicating and suppresses the level of virus detected in the blood stream. Treatment with HAART also protects the immune system.

However, HIV still can silently wreak havoc on the rest of the body’s systems. Many of the drugs in the HAART regimen do not to cross the blood-brain barrier, so patients are still particularly susceptible to brain cell damage.

HIV can penetrate the blood-brain barrier by infecting macrophages and monocytes—types of white blood cells. The viral genome incorporates into the infected cell’s DNA, masking its presence from other immune cells that would detect and kill the infected cell. Eventually this incorporated viral DNA codes for and leads to the manufacture of new viral particles. Infected macrophages bring the virus into the brain and other parts of the body inadvertently, while circulating the body surveying for infections. Several HIV researchers at the IBBS including Janice Clements, Joseph Mankowski and M. Christine Zink, all from the Department of Molecular and Comparative Pathobiology, in an effort to learn how to treat and prevent damage in these tissues, investigate how HIV impairs the brain, nerves and heart.

HIV on a lymphocyte Green HIV covers a red lymphocyte. Source: C. Goldsmith from CDC, Wikimedia

Clements studies the complex molecular mechanisms that contribute to HIV dementia and HIV associated neurocognitive disorder (HAND)—disorders that result in problems with memory and concentration, and dysfunctional motor movements like clumsiness and tremors. Her lab developed the first animal model of HAND using simian immunodeficiency virus (SIV) infection of macaques. Using this animal model, her team learned that brain damage arises from virus-induced inflammation, the body’s reaction to HIV. The infected monocytes in blood travel to the brain and pass the virus onto the brain’s glial cells. Both infected monocytes and glial cells release chemicals that cause inflammation and indirectly damage neurons. She found the mechanism used by HIV to infect glial cells, which is different than the way it infects other types of cells. Clements hopes that understanding how HIV infects cells and causes inflammation in the brain will lead to the design of better antiinflammatory and antiviral treatments for HAND.

Zink investigates potential therapeutics for HAND. Zink’s collaborators in the Department of Neurology have tested a number of existing drugs, often ones that have other effects in the body, to see if they can protect neurons in a dish when subjected to toxic HIV proteins, which normally kill neurons on contact. Drugs that appear to protect cells from dying are passed on to Zink’s team, who administers these drugs to animals infected with SIV. Drugs that help prevent the development of HAND in animals are then sent to other collaborators who test them in clinical trials to see if they can protect HIV-infected individuals from developing HAND. A few drugs identified in this manner already are being tested in clinical trials.

Joseph Mankowski investigates how HIV inflicts damage on the nervous system and the heart. His lab group explores ways to prevent this damage. HIV-infected individuals experience debilitating pain in their feet from nerve damage. Mankowski studies SIV infected animals to figure out the cellular and molecular mechanisms responsible for nerve damage.

HIV-infected individuals also have a higher risk of developing heart disease and failure because of heart damage. According to Mankowski, HIV affects the heart’s ability to fill with blood with each heartbeat. Mankowski is using the SIV animal model to test the FDA-approved HIV drug, maraviroc, for its ability to reduce damage to nerves and heart.

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