Scientists Find New Clues to Fighting HIV
Immune system, genetic discoveries suggest vaccine, treatment strategies
MONDAY, May 14, 2007 (HealthDay News) -- HIV uses a particularly clever mechanism to infect immune system cells, a new study finds, while a second study reveals that certain gene combinations may help slow the progression to AIDS.
Both findings point to intriguing new ways of thwarting HIV, experts say.
"Our immune systems are very effective at fighting HIV -- they are just not quite effective enough," explained Rowena Johnston, vice president of research at the Foundation for AIDS Research (amfAR) in New York City.
She believes the new insights could someday lead to interventions that boost human immune responses to the virus that causes AIDS.
In one study, published May 13 in Nature Immunology, a British team focused on a key point of contact between HIV and immune system agents called dendritic cells. These cells are found in abundance in the mucosal linings of the mouth, genitalia or rectum.
"We are interested in dendritic cells in HIV infection because when you become HIV-positive through sexual activity, they are probably the first cells that HIV encounters," said Johnston, who was not involved in the study. "So, dendritic cells are critical in determining the next step" of whether HIV infection takes hold or not, she said.
In their research, the British scientists found that HIV latches onto a particular surface receptor protein, called DC-SIGN, as it binds with the dendritic cell. That link-up triggers a biochemical signaling cascade that virtually ensures the virus' continued success, the team found.
"[We] found several idiosyncratic aspects of this signal that could favor HIV-1 replication," explained lead researcher Alison Simmons, a clinician scientist at the Weatherall Institute of Molecular Medicine in Oxford. "These include repression of factors that facilitate normal immune responses and activation of factors allowing more effective viral transmission to bystander immune cells."
As HIV grabs onto dendritic cells, it also travels to its ultimate goal, the immune T-cell. The widespread destruction of these T-cells causes the terrible immune deficiency of AIDS.
By binding with dendritic cells via DC-SIGN, HIV evades immune detection early in infection and begins its deadly spread, Simmons said. "It likely is the way in which HIV-1 gains an initial foothold in the body," she said.
The discovery opens up new opportunities for AIDS research, because the inhibition of this DC-SIGN-HIV connection "really is a prime candidate for a drug therapy target," Johnston said. Simmons added that the finding also adds impetus to developing preventive HIV vaccines aimed at the mucosal lining.
A second study goes a long way to explain the variance in disease progression among people infected by HIV. That work, published May 13 in Nature Genetics, focused on two-gene combos that influence the workings of the human immune system as it meets up with the virus.
Comparing the genes of more than 1,500 HIV-positive individuals, a team led by Mary Carrington, principal investigator at the U.S. National Cancer Institute and SAIC in Frederick, Md., found that particular combinations of two genes -- KIR3DL1 and HLA-B -- confer some protection against AIDS progression.
"The variation in those two genes can explain why some people are doing better than others," Carrington said. "There are many combinations of these two genes, and depending on the combination that you have, it's either greater or lesser protection."
KIR3DL1 genes are active on natural killer (NK) cells, which swing into action as part of the "innate" immune system -- the body's less-specific but more immediate line of defense against invading pathogens.
If you get a scratch, for example, "you'll see the area immediately get red and feel warm to the touch -- that's the innate immune system," Johnston explained. Unlike the more targeted "adaptive" immune system, which vaccines take advantage of, this innate system "doesn't need any training," she said. "It recognizes that HIV is a 'foreign thing' and that it should be fought."
The innate system is a rather blunt instrument, though, so it typically doesn't spot and kill all the HIV. "It's a first step," Johnston said. Later on, more efficient "adaptive" immune system cells, such as T-cells, can mop up HIV -- unless, as happens in AIDS, the virus takes them over first.
In the new study, Carrington's team discovered that certain gene combinations confer a more robust "innate" NK cell response, and that response may also help boost the efficiency of adaptive immune system T-cells.
NK cells "are going to start killing HIV-infected cells before cytotoxic T-cells come around," Simmons said. "They appear earlier in the process, and that's why we think that people who have the good [gene] combinations have a jump-start -- they are controlling the virus before you generate the adaptive immune response."
While the discovery has no immediate therapeutic applications, "one thing that we can think about is, can we somehow treat the individual in some way to stimulate NK cell activity early after infection?" Carrington said. In such a situation, "timing is everything," she said.
Johnston said she was also impressed by the connection Carrington's team found between the innate and adaptive immune systems, mediated, in part, by these two genes. "That point of contact may vastly influence your course of HIV," she said.
For more on the fight against HIV/AIDS, visit amfAR.