Division or Multiplication: Exploring the Maintenance of the HIV Reservoir
By Jeffrey Laurence, M.D., and Rowena Johnston, Ph.D.
The remarkable stability of the reservoir of latent HIV in a patient on effective antiretroviral therapy (ART) is measured in many decades. But the mechanisms by which this is achieved are under debate. Two possibilities are: 1) the viral reservoir may maintain its size by infected cells continuing to produce virus that infects other cells while killing the original infected cell; 2) an infected cell may remain quiescent, or inactive, in terms of producing virus but may make copies of itself, with at least one daughter cell containing the virus.
Dr. Sarah Palmer
In last month’s update we noted the work of amfAR fellow Dr. Remi Fromentin of the University of Montreal, who is exploring the very low levels of viral production that are characteristic of many models of the HIV latent state. Writing in the August issue of the Journal of Infectious Diseases, amfAR-funded scientists Dr. Sarah Palmer of the University of Sydney and Drs. Frederick Hecht, Hiroyu Hatano, and Steven Deeks at the University of California San Francisco, with colleagues from the Karolinska Institute in Stockholm, the Rega Institute for Medical Research in Belgium, and the Frederick National Laboratory for Cancer Research and the National Institutes of Health, investigate two much greater contributors to such reservoir stability: growth and differentiation of infected cells.
Dr. Palmer and associates undertook an intensive genetic study of integrated viruses from eight individuals on ART. They isolated the HIV proviruses not only from patients’ blood but also from intestinal and lymph node biopsies. They repeated these studies seven to nine months apart and found that the major home for latent virus—the memory T cell—was maintained mainly by cellular proliferation and longevity of the infected cells itself, rather than by ongoing viral replication.
These data support a critical conclusion: strategies for destroying the latent HIV reservoir might need to be more efficient than the growth of infected cells. And the level of difficulty in achieving this will depend upon exactly where that virus sits inside a particular cell—whether within or apart from a proliferating gene. Dr. Eunok Lee, one of the study’s co-authors, working in the laboratory of Dr. Palmer, won the Lange-Van Tongeren Prize for Young Investigators at the eighth IAS Conference on HIV Pathogenesis, Treatment and Prevention in Vancouver earlier this year for this work.
Dr. Laurence is amfAR’s senior scientific consultant.
Dr. Johnston is amfAR’s vice president and director of research.