Characterizing the reservoirs of Americans versus Ugandans.
Most research on HIV cure is conducted in the United States and therefore on study participants who harbor clade B virus, the most common subtype in the United States. But clade B accounts for only one in eight HIV infections worldwide. Do the lessons we learn from clade B generalize across other subtypes around the world?
A team of researchers that included amfAR grantee Dr. Jonathan Karn characterized the HIV reservoirs in the blood of 68 Ugandan and 50 U.S. study participants. In a tally of all integrated HIV viruses, Americans had larger HIV reservoirs than Ugandans. Since the vast majority of HIV viruses are defective, the researchers also used an assay called EDITS to measure the number of viruses likely to be replication-competent and thus capable of seeding new infections. Again, reservoirs in participants from the U.S. were substantially larger than those of Ugandans. While reservoirs were smaller in Ugandans, the genetic diversity of the viruses within each individual was greater than the diversity in reservoirs in the U.S. Finally, the researchers tested the ability of infected cells to respond to combinations of latency reversing agents (LRAs), an important component of the shock-and-kill approach to curing HIV. Cells in each population of participants reacted similarly to each combination of LRAs.
The team posited two potential explanations – one derived from the viral clades, the other from the immune response – for smaller reservoirs in Ugandans. First, it is possible that genetic differences between clade B versus non-B viruses drive different levels of viral replication and consequent die-off of infected cells. Clade B viruses are also particularly good at evading immune responses that might otherwise target and destroy reservoir cells. Second, the numerous co-infections circulating in low- and middle-income countries (LMIC) may drive a heightened immune inflammatory state, thus boosting the ability of the immune system to kill HIV-infected cells.
While these studies do not provide definitive evidence that different curative approaches will be required for different populations, the researchers concluded that “further, most likely longitudinal, studies are necessary to discern the contribution of viral...and/or host...factors in the HIV-1 reservoir of people living with HIV in LMICs.”
amfAR was a funder of this research.
Dr. Johnston is amfAR vice president and director of research.