Results reported in the Journal of Virology narrow the window of opportunity for therapies.
HIV-1 attacks the immune system earlier than was previously understood, according to a group of scientists. The researchers suggest that intervention must thus be made within days not weeks after transmission.
It was previously believed that the window of opportunity to intervene in the process of HIV-1 infection lay in the three to four weeks between transmission and the development of an established pool of infected CD4 T cells.
“But this new study shows that HIV-1 does a lot of damage to the immune system very early in that time frame, and now we feel that the opportunity to intervene most effectively may range from about five to seven days after infection,” reports Barton Haynes, M.D., the senior author of the study and director of the Center for HIV/AIDS Vaccine Immunology at Duke University Medical Center.
Dr. Haynes explains that an effective vaccine will have to work in two stages. First, it should establish as much immunity as possible before infection. A few days later it should provoke a strong, secondary, broad-based antibody response. “Vaccine candidates to date have pretty much followed a single strategy. Now we know that we need to activate multiple arms of the immune system, and we have a better idea of when to do it,” he points out.
The investigators evaluated 30 people who were newly infected with HIV-1. Plasma from these individuals was sampled every three days for several months before, during, and after the ramp-up phase of infection, when HIV-1 is multiplying rapidly and heading toward its peak viral load.
In measuring the levels of four products of CD4 T-cell death during this period, they were able to track and establish a timetable of the virus’ path. The four byproducts of CD4 T-cell death include TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), Fas ligand, TNF receptor type 2, and plasma microparticles.
The team found that TRAIL levels increased significantly a full week (7.2. days) before peak viral load, which is approximately 17 days after HIV-1 transmission. They hypothesize that during the earliest period of infection, called the eclipse phase, TRAIL may actually initiate or hasten HIV-1’s destruction of CD4 T cells. In contrast, they found that the levels of the other three cell-death products were most significantly elevated during peak viral load.
“What this demonstrates is that significant T-cell death is occurring much earlier during this period than we previously believed, and that TRAIL itself may be a coconspirator in enhancing cell death,” Dr. Haynes explains.
Researchers also examined the effects of cell-death products upon B cells. Through a series of in vitro laboratory experiments with peripheral blood cells, the scientists found that microparticles suppressed levels of IgG and IgA, two classes of antibodies that normally would protect a person against infection. “This is important because many scientists believe that a fast-acting memory B-cell response as well as a T-cell response will be necessary to fight HIV-1,” notes Nancy Gasper-Smith, Ph.D., the lead author of the study and researcher at Duke Human Vaccine Institute, Departments of Medicine.
Investigators from Durham Veterans Administration Hospital, Fred Hutchinson Cancer Research Center, the Statistical Center for HIV-AIDS Research and Prevention, University of Alabama-Birmingham, as well as Cornell University also contributed to the research. Findings are published in the August issue of the Journal of Virology.