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Remnant of HIV Provokes Persistent Inflammation

Antiviral therapy that suppresses HIV-1 viremia does not block release of cell-associated RNA after infection or the inflammatory response it provokes.

A low level of HIV-1 cell-associated (ca)RNA that continues to emerge from infected cells despite antiviral therapy suppression of HIV-1 viremia has now been correlated with markers of inflammatory response by investigators, who suggest this contributes to greater chronic systemic inflammation and age-related diseases experienced by persons living with HIV (PWH).

"Our study set out to identify a possible association between HIV latently infected cells with chronic inflammation in people with HIV who have suppressed viral loads," explained Nina Lin, MD, Division of Infectious Diseases, Department of Medicine, Boston University School of Medicine, Boston, MA and a corresponding author of the report, in a statement released from Boston Medical Center.

Lead author Alex Olson, and colleagues at Boston University describe previous studies that indicate that PWH experience increased rates of age-related conditions such as atherothrombosis, neurocognitive decline and cancer due to increased levels of chronic systemic inflammation; and that optimally treated HIV-1 infected individuals have 5 to 10 years loss in life expectancy and increased medical burden compared to risk-adjusted uninfected counterparts.

"The intact and defective proviruses can yield virus RNA and proteins, which potentially allows the host to recognize the provirus harboring cell.This immune response may account for a possible association between chronic inflammation and intact infectious provirus levels," the investigators posit.

Olson and colleagues sought to ascertain possible associations between age, chronic inflammation and levels of intact proviral DNA and total ca-RNA; as well as examine the possibility of varying levels of inflammation inducing HIV-1 RNA expression in latently infected cells.

Stored frozen samples were obtained for 57 PWH from an existing cohort of a study examining the interaction between HIV and aging. All were receiving combination antiviral therapy for a minimum of 6 months and were virologically suppressed, with plasma HIV-1 RNA levels less than 50 copies/ml.The subjects were stratified into 2 age groups, between 18-35 years (n=23) and >50 years of age (n=34).

In addition to assays for both intact proviral DNA and total ca-RNA, 6 different inflammatory markers were measured: tumor necrosis factor (TNF)-alpha, IL-6, sCD14, sCD163, D-dimer, and CRP.

The investigators report that ca-RNA, but not intact provirus level was positively correlated with plasma D-dimer levels.They found that older individuals had higher D-dimer levels and a trend toward more ca-RNA, but similar levels of intact proviruses.They also found that, although all measured inflammatory markers were relatively higher in the older group, their greater level of inflammation did not induce more HIV-1 transcription in latently infected cell lines.

Olson and colleagues note that the distinction between young and older patients was not binary, but gradated. Applying multivariable linear regression analysis, they found one year of older age associated with 0.007 log10 higher ca-HIV-1 RNA after adjusting for duration of antiviral therapy.

"Our findings suggest that novel treatments are needed to target the inflammation persistent in people living with HIV," indicated a corresponding author, Manish Sagar, MD, in the released statement. "Current antiretroviral drugs prevent new infection, but they do not prevent HIV RNA production, which our results point as a potential key factor driving inflammation in people living with HIV."