Researchers may have finally answered a bedeviling chicken-or-egg question about the relationship between the persistence of HIV in the body during antiretroviral (ARV) treatment and the virus-related immune system activation and inflammation that also continues while people are on ARVs. This finding likely adds further weight to the urgency of diagnosing and treating HIV as soon as possible following infection.
HIV hides its genetic material in cells or locations in the body that remain out of reach of ARVs. This result of this overall effect is known as the viral reservoir, the existence of which prevents standard HIV treatment from curing the virus.
Publishing their findings in PLOS Pathogens, researchers from the AIDS Clinical Trials Group (ACTG) studied 101 people with HIV who had plasma and blood-cell samples taken before they started ARVs, one and four years after beginning HIV treatment, and once more between years six and 15 of treatment. All the participants achieved a viral load considered undetectable by standard laboratory measures and maintained this level of viral suppression for an average of seven years, with some doing so for more than a decade.
The participants experienced the steepest decline in measures of HIV’s genetic material (detected with highly sensitive tests) during their first four years on ARVs; afterward, they still experienced a decline, albeit at a slower pace.
Looking at the samples taken before the participants started ARVs, the researchers identified a correlation between levels of HIV and indicators of immune system activation and inflammation. However, this association ceased after the individuals started treatment for the virus. More specifically, the low levels of HIV found in the samples taken while people were on ARVs did not seem to influence the levels of immune system activation and inflammation during that time.
The investigators ultimately concluded that the levels of both immune system activation and HIV in the pretreatment samples predicted the levels of persistence of the virus and immune activation seen in the samples taken when the participants were on ARVs.
“Our findings suggest that damage to the immune system that occurs before people are started on [HIV] treatment leads to continued immune activation, even though the medicines are keeping the virus in check,” the study’s lead author, Rajesh Gandhi, MD, of the Massachusetts General Hospital Division of Infectious Diseases, said in a press release. “This suggests that diagnosing HIV and starting antiretroviral therapy as soon as possible may prevent the elevated immune activation that can lead to health problems, such as heart disease. The results also suggest that new strategies focused on reducing immune activation may need to be added to novel interventions designed to reduce and eventually eliminate HIV.”


Antiretroviral therapy (ART) reduces levels of HIV-1 and immune activation but both can persist despite clinically effective ART. The relationships among pre-ART and on-ART levels of HIV-1 and activation are incompletely understood, in part because prior studies have been small or cross-sectional. To address these limitations, we evaluated measures of HIV-1 persistence, inflammation, T cell activation and T cell cycling in a longitudinal cohort of 101 participants who initiated ART and had well-documented sustained suppression of plasma viremia for a median of 7 years. During the first 4 years following ART initiation, HIV-1 DNA declined by 15-fold (93%) whereas cell-associated HIV-1 RNA (CA-RNA) fell 525-fold (>99%). Thereafter, HIV-1 DNA levels continued to decline slowly (5% per year) with a half-life of 13 years. Participants who had higher HIV-1 DNA and CA-RNA before starting treatment had higher levels while on ART, despite suppression of plasma viremia for many years. Markers of inflammation and T cell activation were associated with plasma HIV-1 RNA levels before ART was initiated but there were no consistent associations between these markers and HIV-1 DNA or CA-RNA during long-term ART, suggesting that HIV-1 persistence is not driving or driven by inflammation or activation. Higher levels of inflammation, T cell activation and cycling before ART were associated with higher levels during ART, indicating that immunologic events that occurred well before ART initiation had long-lasting effects despite sustained virologic suppression. These findings should stimulate studies of viral and host factors that affect virologic, inflammatory and immunologic set points prior to ART initiation and should inform the design of strategies to reduce HIV-1 reservoirs and dampen immune activation that persists despite ART.

Author summary

HIV-infected individuals who are receiving antiretroviral therapy continue to have low but persistent amounts of virus in blood as well as high levels of immune activation. Elevated immune activation has been linked to medical complications, like heart disease. Whether activation is being driven by or driving HIV persistence is not known. To answer this question, we measured levels of HIV, inflammation and immune activation in 101 HIV-infected individuals before and during long-term antiretroviral therapy. We found that pre-treatment levels of HIV correlated with on-treatment measures of HIV persistence. HIV levels correlated with inflammation and activation before starting therapy but not during long-term treatment, suggesting that virus persistence is not driving or driven by immune activation or inflammation. Higher levels of activation and inflammation before therapy were associated with higher levels during treatment, indicating that immune events that occurred before treatment initiation had long-lasting effects despite sustained control of the virus. These findings should stimulate studies of genetic or viral factors that affect levels of virus, activation and inflammation prior to treatment, and should inform the design of strategies to reduce HIV persistence and dampen harmful immune activation and inflammation in people who are on long-term treatment.
To read the entire study from PLOS's journal, click here.
To read a press release about the study, click here.