The Clinical Significance of HIV Latency

Robert F. Siliciano; Johns Hopkins University School of Medicine, Baltimore (USA)

The existence of a stable reservoir for HIV-1 in resting CD4+ T cells has at least four significant clinical implications.  Recent studies confirm the stability of this reservoir even in the setting of optimal suppression of viremia on HAART.  This finding has contributed to alterations in treatment strategies now that it appears that HIV-1 is intrinsically incurable with antiretroviral therapy alone.  A second important treatment implication is that drug resistant viruses arising due to inadequately suppressive therapy or poor compliance can be permanently archived in this reservoir, permanently limiting treatment options.  The archiving of viral species in the latent reservoir allows the virus to “remember” any mistakes that have been made in treatment that have led to the emergence of detectable resistance.  A third treatment implication is related to treatment decisions in the setting of failure.  A novel assay has been developed to allow physicians to determine how much treatment benefit is due to residual suppression of the resistant virus by the combination of drugs being used and how much is due to ability of the regimen to select against more virulent wild type viruses stored in the latent reservoir.  A final clinical implication of viral reservoirs is related to the issue of low level viremia in patients on HAART.  It is becoming increasingly clear that even in patients who have had prolonged suppression of viremia to below 50 copies/ml, there is some free virus in the plasma.  This virus could represent a low level of replication that continues despite HAART or virus released from stable reservoirs that is unable to replicate further due the effects of the drugs.  Most likely, it is due to some combination of replication and release.  From a clinical perspective, the critical issue is whether the level of replication is sufficient to allow the development of new drug resistance mutations.  With a novel assay, this low level plasma virus has been characterized genotypically.  At this level of viremia, new resistance mutations do not become fixed or accumulate.  Thus in patients who maintain suppression of viremia to below 50 copies/ml, it appears that viral evolution can be largely halted. Although the latent reservoir guarantees lifetime persistence of the virus, current HAART regimen can arrest virus evolution and afford patients the chance for lifelong suppression provided that the problems of toxicity can be overcome.