New findings inform prevention, treatment and cure research and development
The Human Immunodeficiency Virus (HIV) mutates very rapidly and circulates in many different strains. The strain of HIV someone is first infected with, and its capacity to replicate in the body, can have a lasting influence on how the virus disrupts the immune system, according to a study published in Proceedings of the National Academy of Sciences (PNAS).
“These results reinforce our previous findings suggesting that interventions that affect replicative capacity can not only impact disease progression, but also the efficiency of transmission to other people,” says senior author Eric Hunter, co-director of the Emory Center for AIDS Research, Georgia Research Alliance Eminent Scholar and a professor of pathology and laboratory medicine at Emory University School of Medicine. “This informs both vaccine development and eradication strategies.”
The study team included the Zambia-Emory HIV Research Project (ZEHRP), African researchers supported by Imperial College London and the International AIDS Vaccine Initiative (IAVI), and scientists from the Ragon Institute. The researchers obtained HIV samples from 127 newly infected individuals in Zambia and, for each one, derived a measure of the virus’ ability to reproduce in culture. Study volunteers were identified before the provision of antiretroviral therapy, an average of 46 days after the estimated date of infection.
The results confirmed the team’s previous finding that the replicative capacity of the newly established virus drives how quickly infected individuals’ levels of CD4 T cells declined. CD4 T cell counts are a measure of immune system health and how quickly infected individuals could progress to AIDS. Those infected with poorly replicating viruses progressed to low CD4 T cell counts more than two years after those infected with highly replicating viruses.
However, the new, larger study found that the effect of viral replication capacity was very early after infection, and was independent of both initial viral load and whether individuals carried certain protective variants of immune genes called HLA that positively influence immune responses to HIV. People infected with viruses with high replicative capacity had more signs of acute inflammation in the first few months of infection. Their T cells displayed more signs of “exhaustion,” which sets the stage for faster disease progression.
“The effect of viral replicative capacity is just as big as, and independent from, the effect of well-studied protective HLA alleles, which influence whether someone is likely to become an ‘elite controller,’” says Daniel Claiborne, lead author and postdoctoral fellow.
“This suggests lowering viral replicative capacity and the resulting immune activation might have benefits, in terms of morbidity and mortality, for individuals whether they remain treatment naïve or go on antiretroviral therapy. This may have important implications for cure strategies aimed at eliminating the viral reservoir, as individuals infected with low replicative capacity viruses may have smaller latent viral pools that may be easier to eradicate. The implication is that if a vaccine enters the fight against HIV, its contribution doesn't have to be a knockout blow. A vaccine that targets qualities of the virus responsible for replicative capacity could have an important impact on disease progression and secondary transmission.”
The data come from HIV discordant couples enrolled in ZEHRP as part of IAVI’s Protocol C epidemiological study, supported by USAID.
“These findings underscore the huge amount that the HIV vaccine field continues to learn from studies of people in the early, acute states of HIV infection in regions where the epidemic is most severe,” says author Jill Gilmour, executive director of IAVI’s Human Immunology Laboratory (HIL) at Imperial College London. “The study also illustrates increasing African leadership in HIV vaccine research, a pre-requisite for successful long-term collaborative studies on HIV acute infection to inform vaccine design.”
This study was funded by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI64060 and R37 AI51231), the Emory Center for AIDS Research (P30 AI050409), the Yerkes National Primate Research Center (OD P51OD11132), USAID through the International AIDS Vaccine Initiative (IAVI) and Action Cycling Atlanta. USAID administers the U.S. foreign assistance program providing economic and humanitarian assistance in more than 120 countries worldwide.
Replicative fitness of transmitted HIV-1 drives acute immune activation, proviral load in memory CD4+ T cells, and disease progression (D. Claiborne, J. Prince, E. Scully, et al., PNAS)
Editor’s Note: This study also illustrates increasing African leadership in HIV vaccine research. Author Gladys Njeri Macharia of Kenya completed a master’s degree funded by Wellcome Trust and now begins her PhD at IAVI’s Human Immunology Laboratory (HIL) at Imperial College London. Her training is part of a broader IAVI partnership, funded by USAID, to enhance African scientific leadership in the effort to design, develop and evaluate an effective HIV vaccine for Africa. IAVI is working closely in this initiative with its Clinical Research Center partners in Africa as well as Imperial College London and Emory University, among others.
The Zambia Emory HIV Research Project was established in 1994 by Dr. Susan Allen, a professor of pathology and laboratory medicine at Emory University School of Medicine, and is directed by Drs. William Kilembe and Mubiana Inambao. ZEHRP is one of IAVI’s Clinical Research Centers for HIV vaccine development, and focuses on research aimed at prevention of HIV, unplanned pregnancy and neglected tropical diseases.
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Philip T. and Susan M. Ragon Foundation, creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human diseases. The primary initial focus of the institute is to contribute to the development of an effective AIDS vaccine. The Ragon Institute draws scientists and engineers from diverse backgrounds and areas of expertise across the Harvard and MIT communities and throughout the world, in order to apply the full arsenal of scientific knowledge to understanding mechanisms of immune control and immune failure and to apply these advances to directly benefit patients.