The "Mississippi HIV Cure"
Deborah Persaud is Director, Pediatric Infectious Diseases Fellowship Training Program at Johns Hopkins University School of Medicine, Baltimore, USA. Her team together with Doctors at the University of Mississippi Medical Center and the University of Massachusetts Medical School recently described the first case of “cure” in an HIV-infected infant.
Deborah Persaud kindly agreed to answer a few questions.
Alain Lafeuillade: You presented at last CROI in Atlanta the first case of an HIV "cure" in a newborn (for details, see: http://www.hiv-reservoir.net/index.php/the-news/352-functional-hiv-cure-in-an-infant.html). Would you define this "cure" as functional or sterilizing, and why?
Deborah Persaud: This case was designated as a case of functional cure rather than sterilizing cure because of the relatively short period the child has been off antiretroviral drugs, only one year. The word functional was used to serve as a qualifier because we don’t know just yet if virus will return. Also, traces of HIV nucleic acid are still being detected in the child’s cells, although at very low levels. Whether this very low level of HIV DNA and or RNA represents assay error due to very low template level or true imprints of the virus remains to be seen. We realize that our case does not meet the IAS definition of functional cure which involves control of HIV replication with HIV-specific immune responses, but these are not present in our case.
AL: If it is a case of functional cure, where HIV hides and why it does not replicate or induce a specific antibody response?
DP: Given the relatively short time frame, we don’t yet know if replication-competent virus is still present. Longer follow-up is needed and following the evolution of HIV-specific responses off antiretroviral therapy.
AL: The baby was positive at 30 hours of life in terms of HIV RNA and DNA. Could you determine in which type of cells HIV DNA was located?
DP: The HIV DNA test is done on total peripheral blood mononuclear cells, we don’t know specifically what specific cells were infected. However, we showed that on combination therapy, the viral load decayed in biphasic manner in support of HIV infection in short-lived activated CD4+ T cells and longer-lived cells that constitute second-phase HIV decay.
AL: The "cure" is supposed to be due to the fact that at the time of birth, no memory T cells exist yet. Would that mean that HIV reservoirs in other types of cells are not important in terms of viral persistence (macrophages, stem cells…), or that they also did not have time to establish a persistent infection?
DP: Memory cells are very sparse at birth. It means that antigenic exposure was limited in this infant and by curtailing HIV replication promptly, establishment of the central memory and other long-lived reservoirs were prevented from forming. This is a hypothesis that requires further testing. Of course, there may be other, yet unidentified factors, that led to functional cure in this particular infant. Nevertheless, it is a biologically plausible outcome of very early therapy.
AL: Regarding the differences between the immune system in an adult and a baby, how long is the window of opportunity for a therapeutic intervention aimed at inducing HIV "cure"?
DP: That is the million dollar question. Data from Ashley Haase’s group suggest somewhere around 7 days for mucosal transmission. In the Thai study by Dr. Jintanat Ananworich, ART within 14 days in patients with Feibig 1 infection restricted their reservoir to transitional memory CD4+ T cells, though proviral DNA was still present in central memory CD4+ T cells, albeit and significantly lower levels. The same was true for the Visconti cohort reported by Saez-Cirion. Together these data suggest, there is a “window of opportunity”, we just don’t know what that is.
AL: What are the main lessons learned from this case in terms of HIV persistence?
DP: Main lesson from this case that, for infants at least, with prompt therapy we may abrogate HIV reservoir formation that may promote HIV remission and ART discontinuation. We do need to do long-term follow study in the infant to assess for cure and to test whether this can be replicated.
AL: what your next steps are, in particular in terms of clinical trials?
DP: A trial of very early therapy of high-risk HIV exposed infants is under development through the IMPAACT Network sponsored by NICHD, NIAID and NIMH.
Dolgin E. New, intensive trials planned on heels of Mississippi HIV 'cure'. Nature Med 2013; 19 (4): 380-1
Key words: HIV cure, HIV cure strategies, HIV eradication, HIV functional cure, HIV reservoirs