By MIKE MAGEE
In a 1996 JAMA editorial, Nobel laureate Joshua Lederberg MD wrote: “Our fight against microbes is far from over… the odds are tilted in their favor… they outnumber us a billion times and mutate a billion times more rapidly… faced with microbial genes, we humans are mostly at our wits’ end.”
Now, three decades later, our scientists are still in a “battle of wits” with this surprising viral enemy, but even without a vaccine, they have maintained an advantage for humanity. Experts recently confirmed that we are unlikely to have a vaccine by 2030. And it’s not because we haven’t tried. There have been more than 250 official HIV vaccine trials, of which fewer than 10 managed to surpass the safety threshold to prove their effectiveness, and the best performer only had a moderate success rate in triggering some immunity at 31%.
HIV is simply a bad actor according to Professor Anna Durbin of the Johns Hopkins Bloomberg School of Public Health. For starters, it incorporates its chemistry into the host’s DNA genome, blurring the lines between “self” and “non-self.” Most of our successful vaccines focus on a protein portion of the virus envelope or capsule. But the HIV virus has a “glycan shield,” a protein envelope that incorporates about 95 different sugar molecules that protect or disguise the viral protein so that our immune system does not detect it. As one expert described it: “The immune system’s antibodies zoom in on the virus and effectively see a fuzzy cloud of sugars instead of the vulnerable protein underneath.”
The second problem is that the “sloppy genetic duplication” of the virus is riddled with mutations. This produces dozens of different versions, each with infinite subtype variations. This is not typical disciplined viral behavior. The current viral genome, for example, is almost identical to its version from the late 20th century.
And finally, HIV’s favorite invasion target is CD4 lymphocytes, also known as “helper T cells.” That turns out to be the cellular key that unlocks our entire immune system. This virus effectively decapitates the top generals of our defensive force. And yet, we are gaining ground on the virus. How have we done it?
First, focusing on two “workarounds” that trigger “passive immunity” without the help of our own immune machinery. Three decades ago, revolutionary discoveries first offered a ray of hope in the form of antiretroviral drugs. With a variety of different combination therapy approaches, HIV/AIDS emerged as “no longer a death sentence,” but rather a chronic disease, like diabetes, that could be controlled. In the modern era, this effective approach has given rise to PrEP, or “pre-exposure prophylaxis,” a preventative regimen for HIV-negative people who are at risk of contracting HIV.
This regimen, which typically combines the two HIV medications tenofovir and emtricitabine, prevents HIV replication if an individual is exposed to the virus. This reduced transmission by sexual contact by 99% and by illicit injection by 74%. The challenge has been access, especially in underdeveloped countries. But last month, Gilead Pharmaceuticals, in collaboration with the Global Fund and PEPFAR (the President’s Emergency Plan for AIDS Relief), agreed to provide its new antiretroviral drug, lenacapavir (LEN), at cost. In trials, the drug was 99% effective in keeping people HIV negative. Equally important, this is a twice-yearly injectable that could make a big difference in developing countries, especially when it comes to transmission of the virus from HIV+ mothers to newborns during pregnancy and breastfeeding.
Scientists have long known that this population is key to combating HIV/AIDS. The chances of a newborn contracting HIV from an infected mother are 1 in 2. In contrast to unprotected sex (1 in 72) and intravenous drug use (1 in 158), policy makers were clear where to focus. Three decades ago, 1 in 4 children born in Uganda was HIV+. That translated into 32,000 children infected with HIV per year. Today there are less than 5000. How? 1) All future parents get tested for HIV. 2) If they are positive, they receive antiretroviral medications.
The latest WHO statistics show that progress is indeed possible:
“By the end of 2024, 77% of people living with HIV had access to antiretroviral therapy, up from 24% in 2010. Globally, there were 1.1 million pregnant women with HIV in 2024, of whom an estimated 84% were receiving antiretroviral medications to prevent mother-to-child transmission. By the end of 2024, there were 1.4 million children aged 0 to 14 years old living with HIV globally, up from 2.7 million in 2010.” Clearly there is still work to be done. One in six pregnant women with HIV still does not receive treatment.
The second “workaround” is equally promising. It is what the NIH has called a “passive immunization strategy”: monoclonal antibodies. Research in animals, dating back to 2014, found that animals with long-term HIV sometimes develop “broadly neutralizing antibodies” that effectively stop a wide range of different genetic subtypes of HIV. A decade later, synthetic copies of these natural antibodies are being tested. Challenges remain, including the need for continuous infusions, perhaps every six months, to keep formally HIV+ people in “permanent remission.”
A summary report published in Smithsonian Magazine six months ago said: “This year, researchers reported a breakthrough suggesting that a ‘functional’ cure for HIV (a way to keep the virus under control long-term, without constant treatment) may be possible. In two independent trials using infusions of engineered antibodies, some participants remained healthy without taking antiretrovirals, long after the interventions ended.”
The last word goes to Morgan Coulson of the Johns Hopkins Bloomberg School of Public Health, who recently wrote: “The history of HIV vaccine research is a long history of promising ideas that did not translate into protection in large trials. What makes the current moment different is that researchers, for the first time, have shown that they can deliberately guide the human immune system toward producing the type of antibodies known to broadly neutralize HIV. Whether that initial success can turn 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. (Greet/2020)