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Long-term antiretroviral therapy (ART) started during primary HIV infection can reduce plasma HIV RNA to an undetectable level and HIV proviral DNA in resting CD4 T-cells to an extremely low level -- as few as 1 per 1.7 billion cells, researchers from the National Institutes of Health reported in the October 19, 2010 advance online edition of AIDS. Nevertheless, viral replication still resumes and viral load rebounds if ART is interrupted, even after 10 years on suppressive treatment.

The idea of curing HIV -- either eradicating the virus from the body or achieving a "functional cure" that allows cessation of treatment -- has recently received renewed attention.

Soon after the advent of effective combination therapy, some researchers suggested that people who start ART during primary HIV infection -- the first 6 months or so after exposure -- might be able to completely eliminate the virus.

Before long, however, researchers determined that integrated HIV genetic material, known as proviral DNA, remains hidden in a "reservoir" of resting memory CD4 T-cells -- and possibly other types of cells as well -- where it is invisible to the immune system and out of reach of antiretroviral drugs.

A team led by Tae-Wook Chun and Anthony Fauci at the National Institute of Allergy and Infectious Diseases (NIAID) has carried out some of the key studies in this area. In the mid-1990s they started treating a small cohort of patients whose HIV infection was detected very early.

Based on the half-life of latently infected CD4 T-cells and the rate at which plasma HIV levels decay, the researchers suggested that people who start treatment during primary infection might be able to eliminate all virus in resting CD4 cells with prolonged ART, estimated at 7.7 years. Others were skeptical, however, arguing that the reservoir of latent cells harboring infectious HIV might never reach zero.

Chun confirmed these misgivings in a presentation this summer at an International AIDS Society workshop preceding the International AIDS Conference in Vienna ("Towards a Cure: HIV Reservoirs and Strategies to Control Them"); this was followed by the more detailed report in the journal AIDS.

The researchers reported long-term results from 9 members of the cohort who started ART during the first 6 months after infection and 35 patients who started during chronic infection. By now, study participants had maintained plasma viral load suppression (< 50 copies/mL) for a decade, with no "blips" or transient increases.

The authors assessed the size of the HIV reservoir in resting CD4 T-cells. To do so, they collected peripheral blood mononuclear cells (PBMCs) using leukapheresis, a procedure in which blood is withdraw, PBMCs are removed, and the blood is returned to the patient. They first used a PCR assay to measure HIV proviral DNA in purified T-cells, with a limit of detection of 2.6 copies/mcg. They then used a high-input co-culture assay to look for replication-competent virus in a larger population of cells.

Results

• Patients who started ART during primary infection had significantly less HIV DNA in resting CD4 T-cells than those treated later (median 4.6 vs 949.4 copies per 1,000,000 cells).
• 4 out of 9 patients in the early treatment group (44.4%) and 4 out of 35 in the later treatment group (11.4%) had no measurable proviral DNA according to PCR testing.
• High-input co-culture testing detected infectious virus in CD4 T-cells from 8 early treatment patients with undetectable proviral DNA by PCR.
• One early-treated individual on ART for 10.5 years had a very small cellular HIV reservoir, estimated at 0.00064 infected cell per million, or 1 per 1.7 billion resting CD4 cells.
• This man also had undetectable HIV DNA in a sigmoid colon biopsy sample; in contrast, 1 late-treated individual with undetectable proviral DNA in peripheral blood cells also underwent gut biopsy, showing readily detectable HIV DNA.
• The individual with the very small reservoir agreed to a treatment interruption, but experienced viral rebound 50 days after ART discontinuation.

Based on these findings, the researchers concluded, "Our data suggest that a significant reduction in the size of viral reservoirs may be achievable in selected individuals who initiate standard ART early in infection."

"[T]he present study clearly demonstrated that the combination of early initiation of ART, an extended duration of therapy, and a profoundly low HIV burden in CD4+ T-cells did not eradicate HIV, nor did it inde?nitely suppress the re-emergence of plasma viremia," they elaborated in their discussion. "[H]owever, it did lead to a longer period (50 days) of aviremia compared to previous studies (average 9 days) after cessation of antiretroviral drugs."

These findings "suggest that the vast majority of, if not all, infected individuals receiving ART will experience plasma viral rebound regardless of the level of HIV in their CD4+ T-cell compartment at the time of discontinuation of ART," they concluded. "[G]iven re-emergence of plasma viremia in an individual with an extraordinarily low viral burden, therapeutic strategies aimed at specifically targeting these extremely rare HIV-infected cells with novel interventions may be necessary in order to achieve eradication of virus."

Investigator affiliations: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Department of Medicine, University of Washington School of Medicine, Seattle, WW; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

10/26/10

Reference

TW Chun, JS Justement, D Murray, and others. Rebound of plasma viremia following cessation of antiretroviral therapy despite profoundly low levels of HIV reservoir: implications for eradication. AIDS (Abstract). October 19, 2010 (Epub ahead of print).