HIV Latent Reservoir Forms Near the Time of ART Initiation, Researchers Find

While antiretroviral therapy (ART) can suppress HIV infection, ART cannot completely eradicate HIV, which remains in a latent reservoir in CD4-positive T cells during treatment; discontinuation of ART leads to rapid rebound of the virus.

This reservoir forms even when ART is initiated early on in the infection, and while the most widely accepted model of how the reservoir forms involves infection of a CD4-positive T cell as it transitions to a resting state, the dynamics and timing of the reservoir’s formation have been largely unknown.

This month, in a paper in Science Translational Medicine, researchers report that they have now identified evidence showing that initial use of ART alters the host environment to allow the formation or stabilization of the most long-lived HIV reservoir that persists for multiple years during treatment.

The researchers used archived pre-ART viremic samples from the CAPRISA 002 cohort, based in South Africa, to establish a temporal record of viral evolution in 9 women who enrolled from the time of their primary HIV infection. Because the patients enrolled prior to initiating ART, the researchers could use the differences in viral sequences to measure different time points.

Using this viral record, the investigators estimated when the viruses had persisted after more than 4 years during therapy and entered the latent reservoir. In most of the patients, the majority of viruses entered the reservoir around the time that therapy was started; 71% of the unique viruses from the post-therapy latent reservoir were genetically similar to viruses replicating just before ART was initiated.

These findings suggest, say the authors, that ART itself alters the host environment by suppressing viral replication to favor long-lived cells, some of which have latent HIV infection.

“This comes as a big surprise,” said co-senior author Ronald Swanstrom, PhD, professor of biochemistry and biophysics at the UNC School of Medicine, in a statement on the findings. “Our work suggests that if we could understand the reservoir-forming process better, we might be able to intervene at the start of treatment to reduce the majority of the reservoir that forms at this time.”

According to Swanstrom, combining ART with a drug that inhibits the transition of CD4-positive cells to the memory cell state could help prevent some of the viral reservoir from forming in the first place.

“A major goal of current HIV research is to allow people to stop therapy without having the virus come back,” Swanstrom said. “One strategy to achieve this is to eradicate the latent reservoir. Starting with a smaller reservoir could help make that an attainable goal.”

Reference

Abrahams MR, Joseph SB, Garrett N, et al. The replication-competent HIV-1 latent reservoir is primary established near the time of therapy initiation. Sci Transl Med. 2019;11:eaaw5589. doi: 10.1126/scitranslmed.aaw5589.