How long before I’ll need meds? How far will my CD4 cells climb on HAART? Will I get lipo? A Ziagen (abacavir) reaction? These are typical HIVer questions—and the virus, meds and lifestyle issues like diet and exercise only partially determine the answers. The rest is genes. Your DNA is 99.9 percent the same as every other human’s; that other 0.1 percent defines all your inborn differences—including your unique reaction to HIV.
When it comes to HIV, these differences are called host factors—with you as the host—and they distinguish your life with HIV from your buddy’s. They’ve been researched since the dawn of AIDS, but they’ve always ranked secondary to studying the virus’ life cycle and developing antiviral meds. Future HIV treatment may rely as much on genetics as on HAART, so be our guest as we bring up the spotlight on some celebrity host factors.
Host-factor studies are already yielding a new treatment approach. In 1996, the first studies revealed that people with two mutated copies of the CCR5 co-receptor, a chemical door that HIV requires, are nearly uninfectable. HIV uses the CCR5 and CD4 receptor on T cells to enter and infect immune cells called lymphocytes. (Sadly, those with this dual mutation constitute only about 1 percent of Caucasians; other races have even lower numbers.) In September 2003, a CCR5-blocking drug was first tested in an early human clinical trial with good response, and more experimental CCR5-targeted meds are due (see “Inside Story,” page 42).
Anti-CCR5 meds would be the first HIV therapies that don’t attack the virus. CCR5 is a protein in your cells, so it’s not a moving target—it doesn’t mutate like HIV and develop resistance if you miss doses. (Cue applause!)
Other folks aren’t infection-proof but seem to control the virus once they get it. These are long-term non-progressors, a term Bruce Walker, MD, of Harvard’s Massachusetts General Hospital, trades for controllers. Walker has grouped such people into controllers (viral loads under 2,000 without meds) and elite controllers (under 50). One third of those he has studied have the HLA B57 genetic marker (see “HLA’s Photo Gallery” ), which sparks the immune system to respond briskly after infection and continue suppressing the virus. Walker is investigating how the other two-thirds of his subjects manage to check HIV without the B57 variety of HLA (see “Unleash Your Inner Guinea Pig” ). “Some may have an attenuated [weakened] version of the virus,” he says. Even more of a challenge: how to convert controllers’ good fortune into a therapy for those without the beneficial genes.
Predicting Side Effects
Other host-factor research leads to a helpful discovery—if only it were easier to apply. About five to 10 percent of those who take Ziagen, for instance, will get the fever, rash and flulike symptoms of the abacavir-hypersensitivity reaction. If the med is discontinued and restarted, a more severe, sometimes life-threatening reaction can occur. While trying to predict who is susceptible, scientists found that people who react to abacavir seem to have two genetic markers—one is the HLA B57 linked to slow viral progression and good control; the other is a variation in something called the heat-shock protein or HSP. Testing is available only in research labs, and it’s imperfect, revealing only three-fourths of the abacavir-sensitive. Proponents (including GlaxoSmithKline, Ziagen’s manufacturer) say the test could prevent most of the rare (two to four in 10,000) abacavir deaths. Scientists hope that similar genetic profiling of lipodystrophy or neuropathy cases will uncover clues to those conditions, help prevent them and protect HIVers most at risk.
A Host of Possibilities
As Walker puts it, “We haven’t even begun to scratch the surface of research into host factors.” He says so many different elements are simultaneously at work that teasing out crucial factors means studying very large numbers of people. It’s an Olympic marathon, but the prize—bolstering HIVers’ immune systems to fight back without meds—could prove a turning point in the epidemic. Call it the host with the most.
HLA's Photo Gallery
When a virus infects human cell, proteins specific to that virus
appear on the cell surface. As infection-fighting cells patrol the
body, they spot these proteins and compare them with a genetic “mug
shot” that our DNA has encoded. The closer the match, the stronger the
immune response, ranging from no action to marking the infected cell
for death. The stretch of proteins that keeps these mug shots is called
(here goes!) the human leukocyte antigen Class I locus, thankfully
abbreviated to HLA. And the fun continues: Because HLA varies from one
group of people to the next, researchers have branded HLA “families”
with a letter/number designation, like HLA B27 or HLA A2. HIVers who
are host to HLA B57 seem better able to control the virus than those
without that HLA flavor.
Unleash Your Inner Guinea Pig...
...and help unearth the key to long-term med-free survival
What? A study asking why some HIVers can control the
virus—keeping viral loads low and T cells stable—without meds. “There
is an urgent need to understand the factors that allow some to coexist
with HIV and not suffer any apparent ill consequences,” says Bruce
Walker, MD, the study leader. Characteristics of both HIVer host and
viral visitor will be investigated.
Who? They need you if you have never taken HIV drugs and have
always had a viral load under 2,000 RNA copies, or you’re an “elite
controller” whose viral load has never exceeded 50 copies.
Where? The study is being conducted at Massachusetts General
Hospital/ Harvard Medical School, but it’s recruiting HIVers from all
over the U.S. Participants will provide a blood sample through their
local health-care provider.
How? A package with instructions, tubes for blood collection
and consent forms will be provided. Contact Florencia Pereyra, MD:
firstname.lastname@example.org. # 617.726.2306.