Study shows why antiretrovirals cannot eradicate HIV

A study published in the November edition of the Journal of Clinical Investigation has shed new light onto why individuals who have received effective anti-HIV therapy for many years, and have persistently maintained an undetectable viral load, are still unable to eradicate HIV.

In a study involving eleven HIV-positive individuals who had been receiving successful antiretroviral therapy for up to nine years, American and Canadian investigators demonstrated that all eleven patients had CD4 cells infected with HIV that was capable or reproduction, and that most patients also had “considerable” levels of the DNA which HIV produces inserted into cells after infecting both active and resting CD4 immune system cells. The investigators were also surprised to find that most of the persistent HIV was found in active rather than resting CD4 cells.

Antiretroviral therapy can suppress detectable HIV replication to extremely low levels and dramatically improve the health and prognosis of HIV-positive individuals. Reservoirs of HIV are known to persist despite the use of anti-HIV treatment, meaning that eradication of the virus has not proved possible. Pools of latently HIV-infected CD4 cells have been studied as a reason why the virus cannot be eradicated, with attention focused on patients who have taken up to five years of potent ant-HIV therapy.

“The source(s) and extent of ongoing HIV replication in compartments other than resting CD4 T cells in patients receiving effective antiviral therapy for extended periods of time (greater than five years) have not been fully delineated”, the investigators write.

The investigators therefore obtained blood samples from eleven patients who had been taking effective HIV therapy for up to nine years (mean 8.3 years). The patients had a median CD4 cell count of 623 cells/mm³ and all had a viral load below 50 copies/ml. The investigators found HIV in CD4 cells in all eleven patients, “indicating that none of the study participants had eradicated HIV infection”.

Activated and resting CD4 cells were then further examined. The investigators found that HIV proviral DNA was found in both, with significantly more present in activated CD4 cells (p = 0.01). The researchers comment, “in all patients examined, the presence of HIV in resting as well as activated CD4 cells was sustained despite extended periods of undetectable HIV plasma viremia.”

Further tests were performed to see if HIV-infected activated and resting CD4 cells were capable or producing particles of HIV called virions. They found that resting CD4 cells did not produce detectable virions, but that activated cells did.

Finally tests on the genetic structure of HIV isolated from both resting and activated CD4 cells were perfomed. “Evidence for bidirectional HIV infection between resting and activated CD4 cell compartments was observed”, the investigators write.

“To our knowledge this is the first study to examine levels of replication-competent HIV in the CD4 cell compartments of patients who have received effective antiviral therapy for such a long period”, comment the authors.

“Contrary to current dogma, it is the activated CD4 cell compartment that harbors the majority of persisting HIV infection in individuals who have had no detectable viremia for extended periods of time as a result of effective antiretroviral therapy”, they add.

The authors add that by demonstrating the presence of HIV in the activated CD4 cells of patients taking suppressive anti-HIV therapy they have provided “compelling evidence for the contribution of this compartment to the continual reseeding of HIV reservoirs.”

Latent CD4 cells infected with HIV could become reactivated, the investigators suggest, as a consequence of normal responses to infections.

Implications for treatment strategies arising from their findings are suggested by the investigators. These include providing treatment with a reagent to dampen cellular activation and the spread of HIV to other cells. In addition, for patients taking effective HIV therapy, the use of additional antiretrovirals such as entry inhibitors, might be considered as this would further suppress HIV replication.