Timing Is Everything

Research question
An HIV reservoir—latently infected cells beyond the reach of antiretroviral therapy (ART)—is established within about two days post-HIV exposure. While ART can suppress virus to undetectable levels in the blood, dormant, replication-competent cells can be reactivated when ART is interrupted. This threat of viral rebound is why the reservoir is the major impediment to an HIV cure.

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

Findings
Scientists at the University of California, San Francisco, examined 67 people living with HIV (PLWH) given ART during acute infection (up to 100 days after exposure to the virus), as part of their Treat Acute HIV cohort. Over 500 blood samples were collected from these individuals over the course of one year, and levels of DNA representing latent, fully intact HIV as well as defective, non-infectious 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 timing of 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.

Impact
The authors concluded that their study may help personalize cure strategies based on the populations enrolled. For example, PLWH starting ART during a period of chronic infection, but not those accessing ART very early after infection, may require additional interventions to reverse T cell exhaustion. “Thus, these data add to our limited understanding of host viral control at the earliest stages of HIV reservoir stabilization, potentially informing future HIV cure efforts aimed at diverse, global population of [people living with HIV] initiating ART at varying stages of disease.”

amfAR’s role
amfAR was a funder of this research. amfAR grantee Steven G. Deeks of the University of California, San Francisco, was a co-author of the paper.

Original article
http://www.ncbi.nlm.nih.gov/pubmed/38585951

Dr. Laurence is amfAR’s senior scientific consultant.