Timing Is Everything

December 3, 2024

The HIV reservoir—latently infected cells beyond the reach of antiretroviral therapy (ART)—is established within about two days post-HIV exposure. When ART is interrupted, the virus almost always reactivates, and this threat of viral rebound is why the reservoir is the major impediment to an HIV cure. Important questions about the reservoir remain unresolved, however, and some researchers are looking for answers.

How Does the Timing of ART Initiation Impact the Reservoir?

The reservoir is for the most part stabilized when ART is started and then decays slowly, but details of reservoir-decay dynamics, including the impact of timing of ART initiation, initial CD4 counts, and initial viral loads, are unclear.

Dr. Steven G. Deeks of the University of California, San Francisco

University of California, San Francisco, researchers, including amfAR grantee Steven G. Deeks, MD, collected over 500 blood samples over the course of a year from 67 people living with HIV (PLWH) given ART during acute infection. Levels of DNA representing latent, fully intact HIV as well as defective, noninfectious virus were quantified. These data led to mathematical models predicting the decline in HIV reservoirs over time.

Overall, there was a very steep decline in both intact and defective reservoirs within the first five weeks of ART, followed by a much slower decay out to one year. It was faster for PLWH with higher initial CD4+ T cell counts, lower pre-ART virus levels, and earlier ART initiation.

Timing was important. In the first phase of reservoir development, for every week ART use was delayed, the half-life of intact HIV increased by 14 hours, but for every week ART use was delayed in the period 5–24 weeks post-infection the virus half-life increased by 8 days.

The authors concluded that their study may help personalize cure strategies for a diverse, global population of PLWH initiating ART at varying stages of HIV.

Are Latency Reversing Agents Restricted to a Limited Window of Opportunity?

In association with ART, latency reversing agents (LRAs)—drugs designed to reactivate dormant HIV—have been developed over the past decade and tested in a variety of “shock and kill” cure trials, all with disappointing results.

One clue to a new type of LRA came from the fact that latent HIV is first established mainly in HIV-specific CD4 cells (memory cells) and might remain there in people who started ART very early after infection.

A Canadian group led by amfAR grantee Eric Arts, PhD, developed HLP—a dead, HIV-like particle that could activate those specific T cells and wake up dormant HIV. The concept was explored using cells from individuals on ART for two to three years who started treatment during acute HIV infection, or very shortly thereafter. As hoped, in the test tube HLP induced almost 100-fold greater latency reversal than existing agents.

Dr. Eric Arts of the University of Western Ontario (Photo by Megan Morris, Schulich School of Medicine & Dentistry)

But those who started ART at such an early stage represent less than 5% of all people living with HIV worldwide. What about people who started ART later?

The researchers looked at T cells obtained from 32 PLWH from the U.S., Canada, and Uganda who had been on ART for a median 13.2 years. HLPs that could recognize subtypes of HIV found primarily in the West—B—as well as in Africa—A and D—were designed.

HLPs proved equally effective in these groups as in the initial studies, leading to 100 to 1,000-fold more HIV release than previous LRAs. The researchers speculated that multiple injections of HLP into muscle, like a vaccination, could also boost anti-HIV immune responses.

The authors concluded that HLP serves as both a latency reversal agent as well as treatment that can boost HIV-1-specific immune responses, suggesting the possibility of a global, cost-effective HIV-1 cure strategy for the future.

Can Early Treatment in Children Born with HIV Lead to a Functional Cure?

If someone is pregnant and living with HIV but not on treatment, the risk is high that the virus will be transmitted to the child during pregnancy, birth, or nursing. Transmission of the virus means the child must take ART to control HIV for a lifetime. Stopping ART will typically lead to a reactivation of replication-competent HIV and the virus becoming detectable in the blood within weeks.

However, the 2013 case of the Mississippi baby suggested that starting ART early in children who had acquired HIV in the womb might confer remission of the virus. Although that child experienced viral rebound after 27 months off treatment when not in care, a new study presented at the 2024 Conference on Retroviruses and Opportunistic Infections provides proof of concept that early treatment may reduce the HIV reservoir and lay the groundwork for a functional cure, particularly for children.

Researchers monitored 54 infants who acquired HIV in the womb and initiated ART within 48 hours after birth. The infants were then closely monitored for drug safety and viral suppression. Among six children (median age: 5.5 years) who met eligibility criteria and underwent a planned treatment interruption, two experienced viral rebound quickly but four have been able to sustain remission of HIV for at least a year.

Click Here to read more from the December 2024 issue of amfAR INNOVATIONS.