MIKE MAGEE
In a 1996 JAMA editorial, Nobel laureate Joshua Lederberg MD wrote: “The fight against microorganisms is not over yet. The odds are tilted in their favor. They outnumber us by a billion times, and mutations change a billion times faster. In the fight against microbial genes, we humans are primarily at our wits end.”
Now, 30 years later, our scientists are engaged in a “battle of wits” with this incredible viral enemy, but have maintained humanity’s edge even without a vaccine. Experts recently confirmed that a vaccine bullet is unlikely to be available until 2030. It’s not because we haven’t tried. There have been more than 250 official HIV vaccine trials, of which less than 10 have crossed the safety threshold for testing efficacy. Even the best performers had a moderate success rate in inducing some immunity (31%).
According to Anna Durbin, a professor at the Johns Hopkins Bloomberg School of Public Health, HIV is just a bad actor. First, it inserts chemical properties into the host’s DNA genome, blurring the line between “self” and “non-self.” Most of the successful vaccines focus on the protein portion of the viral envelope, or capsule. However, the HIV virus has a “glycan shield.” This protein coat contains about 95 different sugar molecules that protect or camouflage the viral proteins so that the immune system cannot detect them. As one expert explained, “The immune system’s antibodies can approach the virus and effectively see a hazy cloud of sugar rather than the vulnerable proteins underneath.”
The second problem is that the ‘sloppy genetic replication’ of the virus is a mystery accompanied by mutations. This results in dozens of different versions, each with endless subtype variations. This is not typical disciplined virus behavior. For example, today’s measles virus genome is almost identical to the late 20th century version.
And finally, HIV’s favorite target for invasion is CD4 lymphocytes, also known as “helper T cells.” It is the cellular key that unlocks our entire immune system. This virus effectively decapitated the leading generals of our defense forces. And yet we are getting infected with the virus. How did we do it?
First, we focus on two “solutions” to trigger “passive immunity” without the help of our own immune system. Thirty years ago, groundbreaking discoveries first offered a glimmer of hope in the form of antiretroviral drugs. A variety of combined treatment approaches have shown that HIV/AIDS is “no longer a death sentence” but a manageable chronic disease like diabetes. In modern times, this effective approach has led to PrEP, or “pre-exposure prophylaxis,” a preventive therapy for HIV-negative individuals at risk of becoming infected with HIV.
This therapy, which typically combines two anti-HIV drugs, tenofovir and emtricitabine, prevents HIV replication if an individual is exposed to the virus. It reduced transmission through sexual contact by 99% and transmission through illicit injections by 74%. The problem was accessibility. This is especially true in underdeveloped countries. But last month, Gilead Pharmaceuticals agreed to partner with the Global Fund and the President’s Emergency Plan for AIDS Relief (PEPFAR) to provide a new antiretroviral drug, lenacapavir (LEN), at cost. In trials, the drug was 99% effective in keeping individuals HIV-negative. Importantly, it is a twice-yearly injection that could make a world of difference in developing countries, especially when the virus is transmitted from HIV+ mothers to their newborns through pregnancy and breastfeeding.
Scientists have known for some time that this population is key to the fight against HIV/AIDS. A newborn has a 1 in 2 chance of contracting HIV from an infected mother. Compare this to unprotected sex (1 in 72) and IV drug use (1 in 158) and it was clear where policymakers should focus. Thirty years ago, one in four infants born in Uganda was HIV+. This translates to 32,000 HIV-infected children per year. Today it is below 5000. How? 1) All prospective parents are tested for HIV. 2) If positive, antiretroviral medication is administered.
The latest WHO statistics show that progress is indeed possible.
“By the end of 2024, 77% of people living with HIV were receiving antiretroviral treatment, up from 24% in 2010. Globally, there were 1.1 million pregnant women infected with HIV in 2024, of whom approximately 84% were receiving antiretroviral drugs to prevent mother-to-child transmission. By the end of 2024, there were 1.4 million children aged 0 to 14 living with HIV.” Globally, this is a decrease from 2.7 million in 2010.” Clearly, there is still work to be done. One in six pregnant women infected with HIV are not receiving treatment.
The second “solution” is equally promising. This is a monoclonal antibody that the NIH has termed a “passive immunization strategy.” Animal studies from 2014 have shown that animals with long-term HIV sometimes develop “broadly neutralizing antibodies” that effectively stop all of the different genetic subtypes of HIV. Ten years later, synthetically engineered copies of these natural antibodies are being tested. Challenges remain, such as keeping HIV+ patients officially in “permanent remission”, requiring continuous infusions, perhaps every six months.
Six months ago, a brief in Smithsonian magazine said, “This year, researchers reported a groundbreaking discovery suggesting that a ‘functional’ cure for HIV – a method that provides long-term control of the virus without ongoing treatment – may actually be possible. In two independent trials using engineered antibody injections, some participants remained healthy without taking antiretrovirals after the intervention ended.”
The final word comes from Morgan Coulson of the Johns Hopkins Bloomberg School of Public Health, who recently wrote: “The history of HIV vaccine research is a long record of promising ideas that did not lead to protection in large-scale trials. What makes the current moment different is that researchers have demonstrated for the first time that the human immune system can be deliberately induced to produce the kinds of antibodies known to broadly neutralize HIV. Whether early success can be built on to full protection is a key 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 Healthcare Industrial Complex. (Grove/2020)
