Innovative Research Program Provides Deeper Understanding of HIV's Dynamic Process

January 28, 2020

Participants in Last Gift, an end-of-life HIV research program from UC San Diego, donate their blood and their bodies so researchers can uncover all the places that HIV hides, to both fight the disease and stop it. Before each autopsy, the following is read: “From our first breath to our last, each of us tells a unique story. Here, we honor our Last Gift participants for their altruism to further research into HIV and the human condition. We take this moment of silence to honor their gifts and express our gratitude for all the discoveries their selfless donations will yield.”

HIV infection is a persistent, dynamic process. With the ultimate goal of finding a cure, understanding how this disease takes hold is an ongoing investigation, with researchers focused on controlling the spread of the virus once a person is infected. However, investigators often come up against the proverbial wall due to lack of fresh tissue available for testing, in which the viral reservoir has not started to degrade—which could lead to less-than-accurate results.

Study results in a recent issue of The Journal of Clinical Investigation show how important it is to understand how HIV settles into tissues, creating viral reservoirs, in the hopes of stopping or even eradicating them by preventing their dissemination or locking them down.

This patient population was small, coming from the Last Gift study, out of the University of California San Diego. It consisted of 6 male individuals with HIV, with a non-HIV-related terminal illness, whose median age of death was 57.5 years (range, 52-72 years). Four were on continuous antiretroviral therapy (ART) with their viral loads suppressed, and the remaining 2 patients halted their ART at 53 and approximately 70 days prior to death, with rebound viremia. All had been on ART with viral suppression for a mean of 7.5 years (range, 3-14 years) before study enrollment, and all consented to be included in Last Gift, through which they provided blood samples on a regular basis and donated their bodies for rapid autopsy and tissue retrieval within 6 hours of their death.

Before each autopsy, the following is read: “From our first breath to our last, each of us tells a unique story. Here, we honor our Last Gift participants for their altruism to further research into HIV and the human condition. We take this moment of silence to honor their gifts and express our gratitude for all the discoveries their selfless donations will yield.”

“This donation at the end of one’s life is the first of its kind in HIV research, and allowed us to discover all the places HIV hides, even during treatment where the virus is difficult to detect in standard blood tests,” the authors stated.

To better understand the viral reservoirs in the blood and tissue they collected, the study authors sequenced near full-length (FL) env HIV genomes and sensitively quantified HIV DNA. They also collected tissue samples from 28 anatomical sites.

The overall HIV DNA level among the 6 patients ranged from approximately 0 to 658.8 copies/106 cells (median, 55.9; interquartile range, 22.9-126.5). Compared with the patients who remained on ART until their death, the difference in tissue DNA level did not vary from that of the 2 patients who discontinued ART (P >.05). However, evidence did show that “genetically intact FL env variants varied between anatomical compartments” (P = .016), although this was inconsistent among the participants (P = .96).

The viral diversity of HIV RNA showed mixed results. It differed significantly between the 6 patients (P = .057) but not their tissues (P = .51). Meanwhile, there was also significant variation in the identical FL env sequences among the study subjects (P <.01).

These are the main study findings:

  1. HIV RNA repopulated blood plasma throughout the body after ART was stopped.
  2. The largest potential sources of HIV dissemination include gut, lymphoid, and genital tract tissues.
  3. There is a viral exchange of HIV within the central nervous system (CNS), between the blood and CNS, and from lymph nodes to the CNS.
  4. There was low HIV divergence (different strains of the virus) between anatomical sites but high diversity at the recipient site.

Going forward, the study authors believe that the next major goal is to prevent HIV replication if ART is halted. For that, they need new therapies.

“Further improving the health of people with HIV likely means we need to figure out how to clear HIV from its hiding places. This means new therapies,” said Antoine Chaillon, MD, PhD, assistant professor in the Division of Infectious Diseases and Global Public Health at UC San Diego and the study’s lead author.

Reference

Chaillon A, Gianella S, Dellicour S, et al. HIV persists throughout deep tissues with repopulation from multiple anatomical sources [published online January 7, 2020]. J Clin Invest. doi: 10.1172/JCI134815.