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HIV: “Functional vs. Immunological” Cure

A seminal article in the HIV field was published recently in PLoS Pathogens: March 2013:vol 9, issue 3, e1003211, doi:10.1371/journal.ppat.1003211. Investigators working with the hypothesis that the earlier an HIV infection is treated the better, reported that 14 individuals who received antiretroviral therapy within 1.1-2.1 months after infection, and continued for a median of 3 years, had undetectable plasma HIV concentrations for a median of  > seven years after discontinuation of all antiretroviral therapy. For want of a better term the investigators termed this long-term control of viral replication a “functional cure”. Studies of these individuals revealed very low levels of latent viral reservoirs, thereby indicating that early treatment thwarts the establishment of large viral reservoirs as commonly seen in individuals initiated on treatment long after infection has become established.  In this regard, viral cDNA was still detectable in peripheral blood lymphocytes, and when lymphocytes were stimulated in vitro via anti-CD3/28 and IL-2 + IL-7, mature viral RNA could still be detected, so that the investigators could not attribute the lack of detectable plasma HIV to a ‘real’ cure, i.e. eradication of the very last virus, the definition preferred by infectious disease experts. These data are important because they provide proof of principle that HIV infection can be cured, provided the residual viral infection after antiretroviral therapy can be reduced to a very low level, and provided the immune system has not been crippled by the initial infection. There are few, if any, microbial infections that can be cured by antimicrobials alone in an immunocompromized host. Antimicrobials can reduce the microbe numbers to very low levels, but an intact and normally functioning immune system is required to either keep the residual microbes in a latent state or to finally eradicate them. In the case of the many individuals chronically infected before antiretroviral therapy, it is now clear that we must achieve two goals: 1) reduce the residual virus to very low levels, and 2) direct therapy to the immune system to repair any deficiencies before it will be possible to achieve an “immunological cure”.

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