Whittling down reservoirs of HIV-infected cells in the body is thought to be an important first step in the pursuit of a cure. Whether there might be a threshold HIV reservoir size below which the body could contain the virus without additional intervention has been unclear; there have been some reports of individuals who have interrupted antiretroviral therapy (ART) and controlled viral load to undetectable levels for extended periods, most recently from a group of French researchers who described five people (out of a total of 32) maintaining levels below 50 copies/mL for a median of around 6 years of follow up. However, the magnitude of the infectious HIV reservoir in these individuals prior to ART interruption was not reported.
In a study just published online in the journal AIDS, Tae-Wook Chun and colleagues describe the case of an individual treated early in the course of HIV infection who maintained viral suppression for over a decade on ART. Detailed evaluation of the size of the replication-competent HIV reservoir revealed an average of one infected CD4 T cell out of every 1.7 billion CD4 T cells, which the authors describe as “the lowest infectious HIV burden recorded to date in our laboratory.” With the individual’s consent, an exploratory interruption of ART was conducted. Viral load remained below 50 copies/mL for 50 days—longer than the previously described average of nine—but then rebounded to 1,593 copies/mL before falling back below the detection threshold again for around 70 more days. At day 143 after the interruption, viral load climbed to 8,684 copies/mL and at that point ART was restarted.
The researchers conclude that even a tiny number of infected cells can spark viral load rebound upon ART interruption. They go on to state: “In order to achieve a condition under which HIV does not rebound for extended periods of time in the absence of ART, novel therapeutic strategies aimed at more specifically targeting these extremely rare infected cells maybe necessary with or without the use of therapeutic vaccination to boost immune system control of viral rebound.”
AIDS: POST AUTHOR CORRECTIONS, 19 October 2010
Chun, Tae-Wook; Justement, J Shawn; Murray, Danielle; Hallahan, Claire W; Maenza, Janine; Collier, Ann C; Sheth, Prameet M; Kaul, Rupert; Ostrowski, Mario; Moir, Susan; Kovacs, Colin; Fauci, Anthony S
Objectives: Sustained suppression of plasma viremia in HIV-infected individuals is attainable with antiretroviral therapy (ART); however, eradication of virus that would allow discontinuation of ART has been hampered by the persistence of HIV reservoirs. It is of great interest to identify individuals who had received ART for prolonged periods of time with extremely low or undetectable HIV reservoirs and monitor plasma viremia following discontinuation of therapy.
Methods: We measured the size of HIV reservoirs in CD4+ T cells of individuals on long-term ART and monitored plasma viremia following cessation of ART in one individual with an exceptionally low viral burden after a decade of therapy.
Results: We demonstrated undetectable levels of HIV DNA in the blood of eight of 45 infected individuals on long-term ART. Among those eight individuals, the frequency of cells carrying infectious virus was significantly lower in those who initiated ART during the early versus the chronic phase of infection. One individual with undetectable HIV DNA in both blood and tissue and a profoundly low level of infectious virus experienced plasma viral rebound 50 days following discontinuation of ART.
Conclusions: Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection. However, given re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus.