suppressing HIV replication

The Challenge of Curing HIV

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In two HIV-infected patients who had no detectable virus after hematopoietic stem-cell transplantation, HIV rebounded following discontinuation of antiretroviral therapy.

 The success of combination antiretroviral therapy (ART) in suppressing HIV replication led to cautious optimism in the mid-1990s that HIV could be cured. The recognition in 1997 that HIV persists in long-lived reservoirs, however, dashed those hopes. Therefore, the report in 2009 that an HIV-infected man (“the Berlin patient”) was cured of infection after allogeneic hematopoietic stem-cell transplantation (HSCT) for leukemia came as a surprise. After that success, investigators in Boston reported that two HIV-infected men had no detectable HIV following HSCT. (Unlike the Berlin patient, whose donor lacked an HIV co-receptor, the Boston patients received HSCTs from HIV-susceptible donors.) To test the hypothesis that they too may be cured of infection, both Boston patients underwent carefully monitored ART interruption. The results, first reported last year, have now been published.

Before treatment interruption, both patients underwent exhaustive HIV testing: No virus could be detected in peripheral blood, even on sensitive assays using ≥150 million CD4 cells. One patient underwent rectal biopsies, and no HIV DNA was detected. Immune responses against HIV declined in both patients, suggesting that little-to-no virus antigen was present. Genetic testing showed that <0.001% of peripheral blood cells were of host origin.

Following these careful studies, both patients stopped ART under close supervision. In patient A, HIV RNA was first detected in blood about 12 weeks after discontinuing ART, and it rapidly increased to >4 million copies/mL; he developed symptoms of acute retroviral syndrome (ARS) and evidence of HIV-associated meningitis. Patient B went almost 8 months before viremia rebounded to 1.9 million copies/mL; he, too, developed symptoms consistent with ARS. After resuming ART, both patients eventually achieved HIV RNA levels <50 copies/mL.

COMMENT

These cases highlight that techniques for detecting HIV are not yet sensitive enough to confidently predict whether a patient is free of infection; clearly, a high priority is to develop better assays of virus persistence. Another implication is that despite substantial reductions in HIV DNA levels in blood following HSCT — estimated to be >1000-fold in these patients — persistence of virus in even a few cells can rekindle viremia when ART is stopped; indeed, recent modeling suggests >10,000-fold reductions may be needed to prevent HIV rebound. Clearly, this report and that of virus rebound in the Mississippi child emphasize the challenges in eradicating HIV. Although sobering, the results should inspire us to redouble efforts to develop new strategies, such as prodding HIV out of hiding so that it is vulnerable to novel agents or immune-mediated elimination. As an editorialist concludes, “we still have much work to do.”

– See more at: http://www.jwatch.org/na35230/2014/08/01/challenge-curing-hiv#sthash.R9zzkiWb.dpuf