Peripheral blood HIV-1 DNA dynamics in antiretroviral-treated HIV/HCV co-infected patients receiving directly-acting antivirals

Abstract

BackgroundAim was to determine the dynamics of peripheral blood mononuclear cells (PBMC)- associated total HIV-1 DNA in successfully ART-treated HIV/HCV co-infected patients receiving DAA treatment and to explore possible virological hypotheses underlying the phenomenon.MethodsLongitudinal, single-centre study measuring total HIV-1 DNA before the start of DAA, at the end of treatment (EOT), and 3 months after treatment. Univariable and multivariable analyses were used to assess factors associated with HIV-1 DNA increase ≥0.5 Log copies/million PBMC. Episomal 2-LTR forms, residual HIV-1 viremia and proviral DNA quasispecies evolution were also investigated.Results119 successfully ART-treated HIV/HCV co-infected patients were included. Median baseline HIV-1 DNA was 3.84 Log copies/million PBMC (95%CI 3.49–4.05), and no significant variation with respect to baseline was found at EOT and after 3 months of DAA termination. In 17% of cases an increase ≥0.5 Log copies/million PBMC was observed at EOT compared to baseline. HIV-1 DNA increase was independently associated with lower baseline HIV-1 DNA, longer HIV suppression, raltegravir-based ART and previous exposure to interferon/ribavirin for HCV treatment. In none of the patients with HIV-1 DNA increase, 2-LTR forms were detected at baseline, while in 2 cases 2-LTR forms were found at EOT, without association with residual HIV-1 RNA viremia. No evidence of viral evolution was observed.ConclusionsIn successfully ART-treated HIV/HCV co-infected patients receiving DAA, PBMC-associated total HIV-1 DNA was quite stable over time, but some patients showed a considerable increase at EOT when compared to baseline. A significantly higher risk of HIV DNA increase was found, in presence of lower cellular HIV reservoir at baseline. Activation of replicative-competent virus generating new rounds of viral replication seems unlikely, while mobilization of cell-associated HIV from tissue reservoirs could be hypothesized.

Modulation of Monocyte Activation and Function during Direct Antiviral Agent Treatment in Patients Coinfected with HIV and Hepatitis C Virus

“…However, in a previous study, we found a decrease in cell-associated HIV DNA after HCV eradication (11). This discrepancy is in accordance with contradictory results in the literature (11,12,31). It is known that the reservoir of proviral HIV-1 is enhanced in HCV/HIV-coinfected in comparison to HIV-monoinfected patients (32).…”

Killing of Latently HIV-Infected CD4 T Cells by Autologous CD8 T Cells Is Modulated by Nef

“…CD8 T cells interacting with autologous CD4 T cells were fixed on slides and studied by in situ PCR of HIV DNA. The in situ PCR primers (NEC152 and NEC131) are conserved in the HIV LTR sequence and were described before ( 27 , 28 , 38 ). The primers are currently in use by the central virology laboratory of the Israeli Ministry of Health to identify HIV DNA in lymphocytes of newborns from HIV-infected mothers.…”

A Tale of Two Viruses: Immunological Insights Into HCV/HIV Coinfection

“…Most recently, a study of 97 ART-treated subjects reported that HCV/HIV coinfected subjects with chronic HCV infection, as well as HCV/HIV coinfected subjects who have spontaneously cleared HCV, showed higher levels of HIV-DNA in resting CD4 + T cells (CD25 - CD69 - HLADR - ) compared to HIV monoinfected individuals ( 209 ). This increase in HIV reservoir size following DAA therapy may be explained by the mobilization of cells carrying HIV reservoirs from lymph nodes, liver and other tissues into the peripheral blood in response to DAA-mediated reduction of HCV-elicited immune activation and hepatic inflammation ( 10 , 252 ). This is mirrored by the rapid decline of CXCL10 levels in response to DAA therapy, similar to plasma HCV RNA levels ( 253 ).…”

“…Similarly, HCV coinfection is a major cause of non-AIDS-related morbidity and mortality in people living with HIV (PLWH) as it is associated with reduced or slower CD4 + T cell reconstitution after antiretroviral therapy (ART) ( 9 ). In addition, recent studies have reported that direct acting antiviral (DAA)-mediated HCV cure leads to an increase in cell-associated HIV-DNA in the blood of ART-treated PLWH who had low viral reservoirs at baseline, likely as a consequence of viral reservoir mobilization from tissues ( 10 , 11 ). Whether DAA-mediated cure of HCV represents an obstacle to HIV reservoir elimination in coinfected subjects remains an important question to address.…”