By MIKE MAGEE
In a 1996 JAMA editorial Nobel Laureate Joshua Lederberg MD wrote “Our fight with microbes is far from over …odds are tipped in their favor…they outnumber us a billion fold, and mutate a billion times more quickly…pitted against microbial genes, we humans mainly have our wits.”
Now three decades later, our scientists remain in a “battle of wits” with this amazing viral foe, but even without a vaccine, have maintained a slide edge for humanity. Experts recently confirmed that we are unlikely to have a vaccine bullet by 2030. And it’s not because we haven’t tried. There have been more than 250 official HIV vaccine trials, with fewer than 10 making it past the safety threshold to test efficacy – and the best performer only had a moderate success rate in triggering some immunity in 31%.
HIV is just a bad actor according to Professor Anna Durbin at the Bloomberg School of Public Health at Johns Hopkins. To start with, it embeds its chemistry in the host’s DNA genome, blurring the boundaries between “self” and “non-self.” Most of our successful vaccines focus in on a protein portion of the virus envelop or capsule. But the HIV virus has a “glycan shield” – a protein envelope that incorporates around 95 different sugar molecules which shield or disguise the viral protein from detection by our immune system. As one expert described it, “The immune system’s antibodies approach the virus and effectively see a blurry cloud of sugars rather than the vulnerable protein underneath.”
The second problem is the virus’s “sloppy gene duplication” is riddles with mutations. This yields dozens of different versions each with endless subtype variations. This is not typical disciplined viral behavior. Today’s measles viral genome for example is nearly identical to its late 20th century version.
And finally, HIV’s favorite target for invasion is the CD4 lymphocyte, otherwise known as the “Helper T-cell.” That happens to be the cellular key that unlocks our entire immune apparatus. This virus effectively decapitates the lead generals of our defensive force. And yet, we’re gaining on the virus. How have we done it?
First, by focusing on two “work-arounds” that trigger “passive immunity” without the help of our own immune machinery. Three decades ago, breakthrough discoveries first offered a glimmer of hope in the form of antiretroviral medications. With a variety of different combined therapy approaches, HIV/AIDS emerged as “no longer a death sentence,” but a chronic disease, like diabetes, that could be managed. In the modern era, this effective approach has spawned PrEP, or “Pre-exposure Prophylaxis,” – a preventive regimen for HIV negative individuals who are at risk of contracting HIV.
This regimen, generally combining the two anti-HIV meds, tenofovir and emtricitabine, prevents HIV replication if an individual is exposed to the virus. This cut transmission through sexual contact by 99%, and from illicit dug injection by 74%. The challenge has been access – especially in under-developed countries. But las month, Gilead Pharmaceuticals, teaming up with The Global Fund and PEPFAR (President’s Emergency Plan for AIDS Relief) agreed to provide their new antiretroviral drug, lenacapavir (LEN) at cost. In trials, the drug was 99% effective in keeping individuals HIV negative. As important, it is a twice a year injectable that could make a world of difference in developing nations, especially when it comes to transmission of the virus from HIV+ mothers to newborns through pregnancy and breastfeeding.
Scientists have known for some time that this population is key to combating HIV/AIDS. The chances of a newborn contracting HIV from an infected mother are 1 in 2. Contrast that with unprotected sex (1 in 72) and IV drug use (1 in 158), and it was clear to policy makers where to focus. Three decades ago, 1 in 4 infants born in Uganda were HIV+. That translated into 32,000 HIV infected children per year. Today it is less than 5000. How? 1) All expectant parents are HIV tested. 2) If positive, they receive anti-retroviral meds.
The latest WHO stats show progress is indeed possible:
“At the end of 2024, 77% of people living with HIV were accessing antiretroviral therapy, up from 24% in 2010. Globally, there were 1.1 million pregnant women with HIV in 2024, of which an estimated 84% received antiretroviral drugs to prevent mother-to-child transmission. At the end of 2024, there were 1.4 million children aged 0–14 years living with HIV globally, down from 2.7 million in 2010.” Clearly there is still work to be done. One in six pregnant women with HIV is still not under treatment.
The second “work-around” is equally promising. It is what the NIH has labeled a “passive immunization strategy” – monoclonal antibodies. Research in animals, dating back to 2014, found that animals with long-standing HIV sometimes develop “broadly neutralizing antibodies” that effectively stop a whole range of different genetic subtypes of HIV. A decade later, synthetically engineered copies of these natural antibodies are being tested. Challenges remain, including the need for continued infusions, perhaps every six months, to keep formally HIV+ individuals in “permanent remission.”
A summary report in Smithsonian magazine six months ago stated, “This year, researchers reported a breakthrough that suggests a ‘functional’ cure for HIV—a way to keep the virus under control long-term, without constant treatment—may indeed be possible. In two independent trials using infusions of engineered antibodies, some participants remained healthy without taking antiretrovirals, long after the interventions ended.”
The final word goes to Johns Hopkins Bloomberg School of Public Health’s Morgan Coulson, who recently wrote, “The history of HIV vaccine research is a long record of promising ideas that didn’t translate into protection in large trials. What makes the current moment different is that researchers have, for the first time, demonstrated they can deliberately guide the human immune system toward producing the kind of antibodies known to neutralize HIV broadly. Whether that initial success can be built into full protection is the central question for the next decade of research.”
Mike Magee MD is a Medical Historian and regular contributor to THCB. He is the author of CODE BLUE: Inside America’s Medical Industrial Complex. (Grove/2020)
