A “match made in hell” is how Anne Goldfeld describes the association between HIV/AIDS and tuberculosis, two infectious diseases that are causing a co-epidemic in poor countries around the world. It is not just a matter of two deadly diseases converging in one host, but each infection actually makes the other worse. The AIDS virus depletes the immune system, hampering the body’s ability to fight TB, and the immune response to the TB bacterium promotes HIV replication. A third to a half of the 30 million people who have died of HIV worldwide have succumbed to tuberculosis, and TB, on the wane in the pre-AIDs era, has made a ferocious comeback.
Goldfeld, an HMS associate professor of medicine and a senior investigator in the Program in Cellular and Molecular Medicine at Children’s Hospital Boston/Immune Disease Institute, is trying to understand the interaction at its most basic level. In recent work, she has discovered how some strains of Mycobacterium tuberculosis, the causative agent of TB, are more effective than others at triggering the production of immune messengers that drive HIV replication. Her study, published in July in the online journal PLoS ONE, could help explain why some combinations of TB and HIV are more lethal than others, and suggest ways to break up the deadly pair.
The research, a laboratory analysis of cells coinfected with the two pathogens, represents an important piece of Goldfeld’s big picture, but not the only one. When she is not in her Boston lab, she is flying between Boston, Africa and Asia to oversee the activities of the Global Health Committee, an international health organization she cofounded in 1994 and continues to steer. She knows firsthand how the combo of TB, a curable disease, and HIV, a treatable one, is devastating poor and war-affected countries around the world.
“The fact is that despite some local successes, as a whole we are failing to stem the TB–HIV epidemic worldwide,” Goldfeld said. “We need vaccines, we need better drugs and we need to know how to work with the drugs we have better. To succeed, we need to work on multiple levels, to use the tools of discovery to find new cures while ensuring everyone access to medicines and health care.”
As an example, Goldfeld points to Cambodia, where she and colleagues have just finished enrolling 661 patients in a clinical trial to determine the best timing for initiating HIV treatment in people coinfected with TB. The proper timing is critical, since 30 percent of HIV-infected patients die within two months of their TB diagnosis, yet no one has ever tested how to most effectively stage the complicated mixture of antibiotics and antiviral drugs required to save them. The trial, called CAMELIA (Cambodian Early Versus Late Introduction of Antiretrovirals), is funded by the NIH and the French Agence Nationale Recherches sur le SIDA, and is the first of its kind in the world.
While aiming to reduce the 30 percent mortality, Goldfeld is also looking to understand what separates the 70 percent of coinfected patients who live from those who succumb. The possibilities include differences in the strain of TB or HIV involved, as well as variations in host immune response. From past work, she knew that the magnitude of a patients’ immune response to TB could affect HIV replication, but little was known about the effects of different TB strains.
To tackle that question, Shahin Ranjbar, a junior investigator in Goldfeld’s lab and an HMS instructor in pediatrics at IDI, infected purified human blood cells with two strains of TB in combination with HIV. She found that one strain, CDC1551, drove higher levels of virus replication than the other, HN878. Further work revealed that CDC1551 was better at stimulating the immune cells to produce the cytokines TNF and IL-6, proteins that induce cells to pump out more HIV. “This is the first demonstration that TB strains can differentially regulate HIV replication in the test tube and suggests that infection with different strains of TB could result in different HIV viral loads in patients,” Goldfeld said. That may explain some of the variance in patient response seen in Cambodia, and around the world. The results also suggest ways to interrupt the TB–HIV dance.
The results illustrate the synergy that Goldfeld strives for between the clinic and her lab. “Our very basic work in the lab revolves around transcription and gene regulation in the immune system and identifying targets which can later be used for potential new therapies,” she explained. “But the questions I’m stimulated to ask in the lab are directly informed by the clinical observations we are making in Cambodia and elsewhere.”
The GHC offers a model for international health programs, where delivery of care is coupled with research that ultimately aims to improve that care, both in immediate ways and in the long term. At the main CAMELIA trial site, research dollars funded a total makeover of the pulmonary ward at the largest public hospital in Phnom Penh, transforming it from a rundown, understaffed facility where the poorest Cambodians went to die into a bright and modern center of excellence for care, teaching and research. These collateral benefits have already improved patient survival in both arms of the study.
As science improves care, so care advances science. Goldfeld and collaborators at the Pasteur Institute in Phnom Penh are pursuing a series of basic studies within the CAMELIA trial, tracking in detail the immune responses of individual patients during treatment to see how they compare with clinical progress. Past studies have already uncovered an unexpected role for inhibitory immune cells in patients who fail to mount an effective immune response to TB. The work involves a regular shuttling of researchers and clinical specimens between Boston and Cambodia. Complicated, perhaps, but all part of the program for Goldfeld, who says, “Access to care for HIV and TB is a basic human right. Research is essential to deliver on that obligation.”
Students may contact Anne Goldfeld at goldfeld@idi.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The National Institutes of Health; the content of the work is the responsibility solely of the authors. Support for projects in Cambodia and Africa: ANRS, Annenberg Foundation, Jolie- Pitt Foundation and Aeras Global TB Vaccine Foundation.
