Starting antiretroviral therapy too early, before extensive damage to the immune system occurs, improves prospects for a functional cure, according to research presented at the 11th International AIDS Society Conference on HIV Science (IAS 2021) .
However, and unfortunately, most people with HIV are diagnosed and start treatment later., during the chronic infection. Another study found that a combination of antibodies that block interleukin 10 and PD-1 can help control the virus without antiretrovirals, even at this later stage.
Early treatment linked to the smaller reservoir
Soon after initial infection, HIV establishes a long-lasting reservoir of inactive virus in long-lived resting T cells. Although antiretroviral drugs can control viral replication, they do not eliminate these latent viral regimens, which can resume virus production when treatment is stopped — a key barrier to curing HIV.
Edwina Wright, MBBS, PhD, from the University of Melbourne, Australia, and colleagues evaluated the association between breast cancer counts. CD4 T cells and the size of the viral reservoir in people who started treatment at the beginning of the START trial (Strategic Timing of Antiretroviral Treatment). As previously reported, START has shown that people who start treatment with a CD4 count above 500 have a lower risk of illness and death than those who wait until they drop below 350.
Wright and colleagues compared the size of the viral reservoir in 39 people who started antiretroviral therapy with a CD4 count of 500 to 599, 60 who did so with a count of 600 to 799, and 50 who did so with a higher count. of 800.
O "DNA" HIV total was lower in people who started treatment with a CD4 count above 800 compared to those who started with a count of 600 to 799 or 500 to 599 (16, 30 and 68 copies per million cells, respectively) .
HIV 'RNA' in plasma was also significantly reduced in people who started treatment at the highest level of CD4. T-cell activation was lower in people who started with a high CD4 count, according to one measure. Women and older people had lower total HIV DNA than men and younger people.
The findings indicate that people who maintain a CD4 level of at least 800 before treatment "have an enhanced ability to eliminate latently infected cells and may constitute a subgroup that could benefit from interventional healing studies," the researchers concluded. .
In another study, Brian Moldt of Gilead Sciences and colleagues compared the size and diversity of the viral reservoir, as well as HIV susceptibility to the experimental broadly neutralizing antibody elipovimab (formerly GS-9722) in people starting antiretroviral treatment in different stages.
Broadly neutralizing antibodies, currently under study for HIV treatment and prevention, target conserved parts of the virus that change little between strains.
The study enrolled people into four cohorts based on when they started antiretrovirals: the early stages of infection (known as Fiebig stages I or II), when HIV antibodies are first detected (Fiebig stages III or IV). ), late acute infection (three months or less), and early chronic infection (six months or less). The 64 participants were on treatment for three to five years and had a high CD4 count.
Total DNA in T cells was lower in the two groups that started treatment earlier. The late acute group had a lower level than the early chronic group, but the difference did not reach statistical significance. People who started treatment early also had lower viral diversity and greater susceptibility to elipovioma.
"Individuals starting [antiretroviral therapy] during Fiebig I-IV would be an ideal target population for proof-of-concept cure trials due to smaller and less diverse HIV reservoirs," the researchers concluded.
Finally, Caroline Passaes, PhD, of the Pasteur Institute in Paris, and colleagues evaluated the effect of early antiretroviral therapy on post-treatment control, or the ability to maintain viral suppression after stopping medications. Dubbed pVISCONTI (“p” for primate), the study is using a monkey model to learn more about the factors underlying the viral control observed among people in the French cohort of VISCONTI.
The 12 Monkeys
The researchers looked at 12 monkeys with SIV (HIV's simian cousin) who started combination therapy during primary infection (28 days after exposure), 12 who did so during chronic infection (six months after infection), and 17 who remained without treatment. After two years of treatment, antiretrovirals were discontinued.
The viral rebound (defined as a viral load above 1.000) was delayed in monkeys that started treatment during primary infection compared to chronic infection. In addition, 82% of monkeys in the primary infection group achieved post-treatment control (viral load below 400), compared to 25% in the chronic infection group and only 12% in the untreated group. Anti-SIV CD8 T cell activity, which was weak at the time of infection, increased after discontinuation of treatment, particularly in monkeys that started therapy early, and was stronger in post-treatment controllers.
What about later infection?
While researchers agree that starting antiretrovirals too early can improve prospects for HIV control outside of treatment, this offers little help for most people who start therapy later.
So Zachary Strongin, a graduate student at Emory University in Atlanta, and his colleagues studied a functional healing approach that could work for more people. Using a monkey model, they evaluated a combination of antibodies that block interleukin 10 (IL-10) and PD-1 in animals that started antiretrovirals during the initial chronic infection.
IL-10 is an anti-inflammatory cytokine that suppresses T cell activity. Blocking IL-10 leads to reduced T cell survival, reduced expression of inhibitory receptors, and decreased follicular helper T cells, a subset of cells CD4 that harbor latent viruses.
PD-1 is an immunological checkpoint that acts as a brake on CD8 T cells. PD-1 checkpoint inhibitor antibodies – widely used in cancer immunotherapy – restore T cell activity. Both IL-10 production and PD-1 expression are elevated during chronic HIV infection or SIV treated.
These inhibitory signals keep T cells in an inactive state and maintain a persistent viral reservoir. The two mechanisms seem to compensate if only one is blocked, so combining them is a promising approach, Strongin said.
Aggressive strain of SIV
The researchers looked at 28 monkeys with a highly pathogenic strain of SIV that gives rise to high viral loads. Steven Deeks, MD, of the University of California at San Francisco, who was not involved in the study, noted that this is a better model of HIV in humans, as previous healing research often used less pathogenic strains of SIV or HIV that are easier to suppress.
The monkeys started antiretroviral therapy six weeks after infection and remained with them for over a year. After 16 months on antiretrovirals, 10 monkeys were treated with IL-10 and PD-1 antibodies, 10 received only IL-10 antibodies, and eight received a placebo. Antibodies were administered by IV infusion every three weeks. Antiretrovirals were discontinued after the first four doses, and experimental therapy was then continued on its own for another 14 weeks.
Viral Rebound in Less Than Three Weeks
All monkeys experienced viral rebound within three weeks of stopping antiretrovirals, but viral levels reached significantly lower levels in those who received IL-10 antibodies alone or with PD-1 antibodies. After the initial jump after stopping treatment, the new viral setpoint was established at around 50 copies in the dual antibody group, compared to around 100.000 in the other two groups.
Nine of 10 animals that received both antibodies experienced viral suppression below 1.000 copies at some point after viral rebound, compared with four in the IL-10 antibody group and only one in the placebo group; some even had a stable undetectable viral load. Viral levels were "remarkably low" due to the highly pathogenic SIV strain, Strongin said.
After the final dose of antibodies, those in the combination group had a 4 log reduction in viral load. compared to their pretreatment level, while those in the other two groups had a 1,7 log reduction. Most in the combination group maintained viral control for several weeks after stopping the antibodies. However, the experimental treatment cannot be considered a cure as the viral rebound occurred after the antibodies were discontinued.
No Adverse Effects
None of the treated animals had systemic adverse events, but some had localized mucosal inflammation. Strongin said a better understanding of these effects "will be critical to inform future studies."
The combined IL-10 and PD-1 antibodies led to "sustained and robust viral control in the absence of antiretroviral therapy in most animals", concluded Strongin, adding that the results "have real potential to achieve viral remission".
Ttranslated by Cláudio Souza, from the original in New Approaches for HIV Cure Research