Breast Milk Antibody Fights HIV But Needs Boost

Breast milk antibody both neutralizes human immunodeficiency virus (HIV) and kills HIV-infected cells, according to a paper in the September 2011 issue of the Journal of Virology.

"This finding indicates that enhancement of these responses through vaccination could help reduce HIV transmission via breastfeeding," says corresponding author Sallie Permar of Duke University, Durham, NC. While HIV-specific antibodies have been identified in breast milk, this is the first study to investigate the virus-blocking functions of these antibodies.

Nonetheless, the statistics indicate that breast milk antibodies are doing an incomplete job of protecting babies from HIV transmission. Nearly half of the 350,000 new infant HIV infections occurring annually are transmitted via breast milk. Permar's study provides perspective: it shows that the magnitude of anti-HIV responses in breast milk is low compared to those in plasma.

Thus, the need to enhance that response. Fortunately, the study's results suggest that current systemic HIV vaccine candidates may be effective in enhancing anti-HIV functions of breast milk antibody, and reducing postnatal HIV transmission. Permar et al. found that breast milk antibody's activity against HIV and HIV-infected cells is mediated by IgG antibodies that originate in the blood stream, rather than IgA antibodies, which are produced in the mammary gland.

The alternative to immunologic intervention, formula feeding, "is not a viable option for reducing this mode of transmission in resource poor areas with high HIV prevalence, as it is associated with high infant mortality from diarrhea and respiratory illnesses," says Permar. "While maternal and/or infant antiretroviral prophylaxis during the period of breastfeeding is effective in reducing infant transmission, HIV transmission continues to occur in the setting of optimal prophylaxis and the effects of this long-term prophylaxis on infant growth and development are not known. Moreover, long-term prophylaxis is a challenge for resource poor areas." But a maternal or infant vaccine would be ideal for eliminating post-natal HIV transmission, she says.

(G.G. Fouda, N.L. Yates, J. Pollara, X. Shen, G.R. Overman, T. Mahlokzera, A.B. Wilks, H.H. Kang, J.F. Salazar-Gonzalez, M.G. Salazar, L. Kalilani, S.R. Meshnick, B.H. Hahn, G.M. Shaw, R.V. Lovingood, T.N. Denny, B. Haynes, N.L. Letvin, G. Ferrari, D.C. Montefiori, G.D. Tomaras, S.R. Permar, and the Center for HIV/AIDS Vaccine Technology, 2011. HIV_specific functional antibody responses in breast milk mirror those in plasma and are primarily mediated by IgG antibodies. J. Virol 85:9555-9567.)

Small Molecule Hobbles Dengue In Vitro and In Vivo

A novel compound inhibits dengue virus, as well as other closely related important human pathogens. The research is published in the September 2011 issue of the journal Antimicrobial Agents and Chemotherapy.

Dengue virus causes an estimated about 50 million infections annually, resulting in half a million hospitalizations, and a 2.5 percent mortality rate, according to the World Health Organization. Neither antivirus therapy nor vaccines exist against dengue. The newly discovered inhibitor is also active against fellow flavivirus family members including West Nile virus, yellow fever virus, Japanese encephalitis virus, and tick-borne encephalitis virus. The compound works by preventing translation of RNA to protein, according to the report.

In the study, the researchers identified the small molecule inhibitor via high throughput screening of Novartis compound libraries, says corresponding author, Pei-Yong Shi of Novartis Institute for Tropical Diseases, Singapore. They then refined the original molecule to give it greater metabolic stability. Tests in a dengue mouse viremia model showed that "this compound significantly reduced peak viremia, demonstrating the in vivo efficacy of the inhibitor," according to the report.

However, despite the fact that the compound selectively inhibits protein translation in flaviviruses, in in vitro tests, it nonselectively inhibited viral and host translation. That raised the specter of side effects, and indeed, tripling the experimental dose in the mouse model caused significant side effects, according to the report. Thus, the therapeutic window needs to be widened before the compound will be ready for clinical testing, the researchers report.

The compound is being developed under the auspices of the Novartis Institute for Tropical Diseases, which aims to develop novel therapeutics for neglected diseases, and to provide these new medicines to poor patients at cost prices," says Shi. "Dengue poses a public health threat to 2.5 billion people worldwide," most of them living in poverty or near poverty.

(Q.-Y. Wang, R.R. Kondreddi, X. Xie, R. Rao, S. Nilar, H.Y. Xu, M. Quing, D. Chang, H. Dong, F. Yokokawa, S.B. Lakshminarayana, A. Goh, W. Schul, L. Kramer, T.H. Keller, and P.-Y. Shi, 2011. A translation inhibitor that suppresses dengue virus in vitro and in vivo. Antim. Agents Chemother. 55:4072-4080.)

Elite Controllers Block Integration of HIV DNA Into Host Genome

Alone among those infected with HIV-1, so-called elite controllers spontaneously maintain undetectable levels of viral replication even absent the benefit of anti-retroviral therapy. Now Mathias Lichterfeld of the Massachusetts General Hospital, Boston, and Xu Yu of the Ragon Institute show that in elite controllers, integration of HIV-1 DNA into the host chromosomes of CD4 T cells - the main target cells of HIV-1 - is markedly reduced in comparison to those whose infection has run a more normal course. "[Elite controllers] behave like people who get effective antiretroviral treatment, despite the fact that they don't," says Lichterfeld.

In the study, the researchers removed CD4 T cells from elite controllers, from random HIV-1 negative persons, and from HIV-1 infected persons with progressive disease, and infected those cells with HIV-1 in the laboratory. While HIV-1 successfully integrated into both reference populations' CD4 T cells far more effectively than into those of elite controllers, the researchers found higher levels of unintegrated, extrachromosomal HIV-1 DNA floating around in the elite controllers' CD4 T cells.

"Overall, this suggests that the process of chromosomal integration of HIV-1 is somehow inhibited in elite controllers," says Lichterfeld. Now poorly understood, the mechanism likely involves a synergistic interplay between multiple innate and adaptive immune defenses, he says.

"We think that these subjects can really teach us a lot about how immune-mediated control can work under real-life circumstances," says Lichterfeld. "If we were to understand in detail what's going on in these patients, we might be able to develop some sort of intervention that could protect people against HIV-1."

This report is consistent with a paper published earlier this year which showed that elite controllers have low levels of chromosomally integrated HIV-1 DNA, and higher levels of extrachromosomal, 2-LTR circular HIV DNA, as compared to patients on highly active anti-retroviral therapy (HAART) (PLoS Pathog. 7:e1001300).

The research is published in the September 2011 issue of the Journal of Virology.

(M.J. Buzon, K. Seiss, R. Weiss, A.L. Brass, E.S. Rosenberg, F. Pereyra, X.G. Yu, and M. Lichterfeld, 2011. Inhibition of HIV-1 integration in ex vivo-infected CD4 T cells from elite controllers. J. Virol. 85:9646-9650.)

Danger Signal Limits Hepatitis C Infection

Despite the fact that hepatitis C virus (HCV) persists chronically in about 80 percent of those infected, some liver cells remain free of the virus even after many years. Now Sung Key Jang of Pohang University of Science and Technology, South Korea, et al. explain that paradox. During chronic HCV infection, a cellular protein, HMGB1, helps restrain viral reproduction. That prevents HCV from sweeping the liver, and results in a lower blood burden of virus than in the case of hepatitis B. This first description of HMGB1-related responses triggered by HCV infection is published in the September 2011 issue of the Journal of Virology.

The researchers show further that HCV-infected cells secrete HMGB1 proteins into the extracellular milieu. There, these proteins trigger a receptor on the cytoplasmic membrane, called TLR4, causing both an interferon response, which fights the virus, and an inflammatory response.

Two different responses coming from the same receptor at the same time is a common phenomenon. But that can make designing drugs all the more complicated. Boosting the interferon response could vanquish the virus, but the inflammatory response would be harmful. However, Jang says that it might be possible to get the one response without the other. If HMGB1 in the TLR4 receptor is like a hand that fits nicely in a glove, thus triggering both responses, perhaps a drug could be fashioned which could fit a piece of the receptor, like two fingers in a glove, thus triggering only the interferon response. This is an unpublished hypothesis, says Jang, but one that his group is working on.

In the paper, the researchers note that HMGB1 is a "danger" signal. The Danger model of immunology, derived by Polly Matzinger of the National Institute of Allergy and Infectious Disease, NIH, posits that immune responses are initiated by signals from damaged cells. Rather than distinguishing between "self" and "nonself," as per conventional wisdom, the Danger model suggests that when cells are stressed, injured, or killed (by external forces rather than through so-called programmed cell death), they give off alarm signals that activate the immune system to clear the damaging agents.*

About 18 million people worldwide are infected with HCV. That virus causes inflammation (hepatitis), massive death of liver cells (cirrhosis), and hepatocellular carcinoma. Liver cancer, primarily hepatocellular carcinoma, which is also caused by heptatitis B virus, is the third leading cause of cancer deaths worldwide, and the ninth leading cause of cancer deaths in the United States, according to Morbidity and Mortality Weekly Report.

(J. Ha Jung, J. Hoon Park, M. Hyeok Jee, S. Ju Keum, M.-S. Cho, S. Kew Yoon, and S. Key Jang, 2011. Hepatitis C virus infection is blocked by HMGB1 released from virus-infected cells. J. Virol. 85:9359-9368.)