Date Published: June 17, 2019
Publisher: Public Library of Science
Author(s): Leila Bertoni Giron, Simone B. Tenore, Luis Mario Ramos Janini, Maria Cecilia Araripe Sucupira, Ricardo Sobhie Diaz, Cecilio López-Galíndez.
Residual HIV-1 replication among individuals under antiretroviral therapy (ART) relates to HIV micro-inflammation.
To determine the levels of residual HIV replication markers among distinct subgroups of antiretroviral-treated individuals.
One hundred sixteen patients were distributed into 5 treatment groups: first-line suppressive ART with a non-nucleoside analog reverse-transcriptase inhibitor (NNRTI) (n = 26), first-line suppressive ART with boosted protease inhibitors (PI-r) (n = 25), salvage therapy using PI-r (n = 27), salvage therapy with PI-r and raltegravir (n = 22) and virologic failure (n = 16). Episomal and total DNA quantitation was evaluated. ELISA was used for HIV antibody and LPS quantitation.
Episomal DNA was positive in 26% to 38% of individuals under suppressive ART, and it was higher among individuals experiencing ART virologic failure (p = 0.04). The HIV proviral load was higher among patients with detectable episomal DNA (p = 0.01). Individuals receiving initial PI-r treatment presented lower HIV antibody (p = 0.027) and LPS (p = 0.029) levels than individuals receiving NNRTI. There was a negative correlation between episomal DNA quantitation and the duration of suppressive ART (p = 0.04), CD4+ T-cell count (p = 0.08), and CD8+ T-cell count (p = 0.07).
Residual HIV replication has been inferred among individuals under suppressive ART according to episomal DNA detection. Residual replication may decrease with longer periods of suppressive ART and higher levels of CD4+ and CD8+ T cells. The relationship between episomal DNA and total DNA suggests there is a replenishment of the proviral reservoir with impacts on HIV persistence. Lower antibody and LPS levels among patients with initial PI-r ART suggest these regimens may more effectively suppress HIV and have a higher capacity to decrease the HIV antigenic component.
The deleterious effects of HIV are directly related to viral replication, which leads to inflammatory processes, such as the activation of CD4+ and CD8+ T lymphocytes . Maintaining viral replication at lower levels is critical for the reduction of cellular activation and co-morbidities related to HIV-1 infection. However, the antiretroviral therapy (ART) currently used does not completely suppress viral replication. Up to 80% of patients with undetectable viral loads according to commercial tests show an average of 3.1 copies/mL of residual viral load when ultrasensitive tests are used [2, 3]. Although the stability of episomal DNA is not completely understood, extrachromosomal DNA is useful as a surrogate marker of HIV-1 replication when the HIV viral load is not detectable by currently available methods . Other markers that relate to HIV-1 replication among individuals under ART include proviral HIV DNA  and the quantitation of HIV antibody levels  or markers that relate to bacterial translocation . ART regimens differ in potency as well as in the distinct genetic barriers they create or effects they have in each step of the HIV replication cycle to alter viral dynamics. For this reason, the evaluation of circular HIV DNA could be used as a tool to indirectly compare the effectiveness of these distinct regimens on residual HIV replication. Therefore, this study aimed to analyze surrogate markers of the residual replication rates of HIV-1 among individuals receiving different antiretroviral regimens. We hypothesize that drugs from different classes and previous ART virologic failure will affect surrogate markers of HIV residual replication.
As mentioned before, antiretroviral treatment is not fully suppressive in all individuals, as shown by the detection of viremia in individuals evaluated with ultrasensitive viral load assays  or withtests for cell-associated RNA . Interestingly, this residual viremia may come from so-called sanctuaries, such as the gastrointestinal tract . As such, they form an obstacle for achieving a sterilizing cure. Furthermore, specific HIV inflammation inferred by the levels of T-cell lymphocyte activation persists among antiretroviral treated individuals in spite of undetected viral loads . Efforts and strategies to mitigate HIV-related inflammation is currently a major task. One effective way to decrease this inflammation would be to maximize the antiretroviral suppressive effect, thus reducing residual replication.