HIV’s 'Pathogenic Landscape' Research Identifies New Drug Targets

A University of California at San Francisco (UCSF)–led team of researchers believes it has succeeded in mapping every apparent physical interaction HIV makes with components of the immune system cells it infects, work the researchers say should ultimately reveal new therapeutic and curative drugs. The encouraging findings are reported in two papers published in the December 21 issue of Nature.

As highlighted in one paper, authored by Nevan Krogan, PhD, of UCSF and his colleagues, HIV has a small genome, and therefore its replication relies heavily on the cellular machinery of its host, notably human CD4 cells. As the development of new therapies and curative approaches ultimately requires researchers to fully understand these interactions—and uncover ways to both prevent these interactions from occurring and disentangle them once the connections have occurred—it is necessary to first identify which cellular components come into physical contact with HIV’s proteins.

In its paper titled “Global Landscape of HIV-Human Protein Complexes,” Krogan’s group highlights the methods it undertook to discover 497 connections between HIV and 435 individual human proteins. Only a handful of these connections, the authors note, have been recognized thus far by scientists.

Disrupting these connections may interfere with HIV’s lifecycle, the authors note, and the existence of so many new connections suggests there may be several novel ways to target the virus.

In the second Nature paper, Krogan and his colleagues investigated one such connection in detail. They discovered that an HIV protein called Vif makes a physical connection with a human protein called CBF-β, hijacking its function. When this occurs, Vif is able to recruit CBF-β and, when working in tandem with other proteins in the body, can dismantle an enzyme called APOBEC3G, a natural defense against viral replication in the human body.

Another example, highlighted in the first paper, includes the Pol interaction network. The gene Pol is the source of several important viral proteins that are essential to HIV’s infectious lifecycle. Four major antiretroviral drug classes block Pol’s three major proteins: reverse transcriptase (RT), protease and integrase. Krogan’s group documented dozens of interactions between RT, protease and integrase and human proteins, most of which were not previously known to exist.

Multiple virus-host interactions involving other HIV proteins were also highlighted. According to Krogan’s group, there are numerous interactions between human proteins and proteins produced by the Gag gene, which help form the internal architecture of virus particles assembled inside infected cells. The same goes for HIV’s Env gene, which produces the large envelope proteins Gp160, Gp120 and Gp41 that protrude from HIV’s membranes and facilitate its entry into human cells—these proteins interact with dozens of human proteins, only a handful of which were previously known.

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