Can medical advances cure HIV?

Over­shad­owed since 2020 by SARS-CoV­‑2, the Human Immun­od­e­fi­cien­cy Virus (HIV), is respon­si­ble for a pan­dem­ic that has last­ed for over 40 years and has already been the cause of around 40 mil­lion deaths. In a pre­vi­ous arti­cle, we report­ed on the cur­rent sit­u­a­tion of Acquired Immun­od­e­fi­cien­cy Syn­drome (AIDS) in the world and on the progress of treat­ments and pre­ven­tive approach­es. A pub­li­ca­tion in the jour­nal Nature in Feb­ru­ary this year, describ­ing a patient who was demon­stra­bly HIV-free¹, has brought a fun­da­men­tal ques­tion back to the fore­front: can HIV be cured?

Today, thanks to tri-ther­a­py, AIDS is now con­sid­ered a chron­ic dis­ease – it is pos­si­ble to live with HIV, but it can­not be cured. This is due to a speci­fici­ty of retro­virus­es, the fam­i­ly to which HIV belongs, which are capa­ble of insert­ing their genet­ic mate­r­i­al into the cells they infect. The viral genome can there­fore remain hid­den in the body and restart the pro­lif­er­a­tion of the virus if treat­ment is stopped. This per­sis­tent viral reser­voir is the sub­ject of much research and, although we know more and more about it², it remains impos­si­ble to elim­i­nate it effec­tive­ly. With very few exceptions. 

It is always dif­fi­cult to talk about a cure for dis­eases that are known for being per­sis­tent, such as can­cer or AIDS. Even if no trace of the dis­ease is detect­ed for long peri­ods of time, there is no guar­an­tee that this sit­u­a­tion will be per­ma­nent. Spe­cial­ists gen­er­al­ly pre­fer the term remis­sion and only use the term cure after a sig­nif­i­cant peri­od of time, the length of which is nec­es­sar­i­ly arbi­trary and varies from case to case.

How­ev­er, three patients appear to have been “cured” of HIV, all of whom had sim­i­lar treat­ment his­to­ries. The first, Tim­o­thy Brown, is known as the “Berlin patient”³. Hav­ing devel­oped leukaemia, he was treat­ed with a bone mar­row trans­plant in 2007 to replace his blood cells. In the absence of detectable HIV, his tri-ther­a­py was stopped in 2008 and no viral rebound was observed until his death in 2020⁴. A decade lat­er, in 2016, Adam Castille­jo, the “Lon­don patient”, under­went a mar­row trans­plant to treat lym­phoma. His HIV treat­ment was stopped the fol­low­ing year and, after more than five years, the infec­tion has still not returned⁵. Since Feb­ru­ary this year, the anony­mous “Düs­sel­dorf patient” has been added to the list! Hav­ing under­gone a mar­row trans­plant in 2013 to fight leukaemia, his anti­retro­vi­ral treat­ment was stopped in 2018, with no resump­tion of the dis­ease since. To under­stand how these trans­plants have helped con­trol HIV, we need to look at mol­e­c­u­lar biol­o­gy a little.

The few cas­es of HIV cures remain more inter­est­ing for research than direct­ly promis­ing for patients.

To infect a cell, HIV needs to enter it. This requires the enve­lope pro­tein on the sur­face of the virus, which can be thought of as a mol­e­c­u­lar key, to meet the right locks. The main one is the CD4 recep­tor, which is found in par­tic­u­lar on T4 lym­pho­cytes. But it is not the only one, a co-recep­tor is also involved: it can be the CXCR4 pro­tein or the CCR5 pro­tein. The mar­row donors select­ed for the trans­plants of the Berlin, Lon­don and Düs­sel­dorf patients had been care­ful­ly cho­sen. In addi­tion to being com­pat­i­ble with the recip­i­ents, they all pos­sessed a muta­tion in the gene encod­ing the CCR5 pro­tein. Called Δ32, this pre­vents the entry of HIV into the cells. After their trans­plants, the immune sys­tems of all three patients rebuilt them­selves from mar­row car­ry­ing this muta­tion, and the HIV in their bod­ies found itself fac­ing a closed door.

The idea of a cure for HIV is excit­ing. How­ev­er, there are a num­ber of lim­i­ta­tions that pre­vent this mar­row trans­plant approach from being a treat­ment that can be applied across the board. The first is that the med­ical pro­ce­dure is extreme­ly cum­ber­some, can lead to death in about 10% of cas­es and has sig­nif­i­cant side effects. Its use is legit­i­mate as a last resort in the case of treat­ment-resis­tant can­cer, but in the case of HIV, the ben­e­fit-risk bal­ance of triple ther­a­py is indis­putably better. 

More­over, in order to car­ry out such a trans­plant, a com­pat­i­ble donor must be found (which is already a del­i­cate mat­ter, as the cam­paigns call­ing for mar­row dona­tion remind us⁶) who is also a car­ri­er of the Δ32 muta­tion. How­ev­er, this muta­tion is rare. Its fre­quen­cy varies accord­ing to the pop­u­la­tion but, at best, it is present in only about one per­son in a hun­dred: a rare find. An alter­na­tive is to pro­duce a mixed graft, from umbil­i­cal cord stem cells and a dona­tion, both of which are par­tial­ly com­pat­i­ble. This approach was used in 2017 to treat a mixed-race woman with HIV and leukaemia. In March 2023, it was announced that the virus remains unde­tectable in her body despite her treat­ment hav­ing been stopped over two years ago⁷. It is pos­si­ble that this remis­sion will turn out to be a cure!

Final­ly, although it has received less media atten­tion, not all patients who received mar­row trans­plants with the Δ32 muta­tion have been cured of HIV. Whether this is due to prob­lems with the trans­plant and the can­cer it was intend­ed to com­bat⁸ or to adap­ta­tions of the virus to dis­pense with CCR5 by using the CXCR4 co-recep­tor instead⁹, suc­cess is far from systematic. 

The few cas­es of HIV cured to date are there­fore more inter­est­ing for research than direct­ly ben­e­fi­cial for patients, as are those of the few peo­ple who seem nat­u­ral­ly able to con­trol the virus¹⁰. The search for an effec­tive vac­cine is com­pli­cat­ed by the virus’ capac­i­ty to adapt: all promis­ing can­di­dates have end­ed up being dis­ap­point­ing in phase 3 clin­i­cal tri­als, as the recent ter­mi­na­tion of the Mosaico tri­al reminds us¹¹. How­ev­er, even if we can­not cure HIV, we are far from help­less in the face of this virus! Pre-expo­sure pro­phy­lax­is, or PreP, con­sid­er­ably reduces the risk of catch­ing it¹² and treat­ments now make it pos­si­ble to live with this virus with­out being con­ta­gious¹³.