Detection of Infectious HIV in Circulating Monocytes From Patients on Prolonged Highly Active Antiretroviral Therapy

Cordero

Cytometry Part B Clinical

et al. 2006

Background: HIV-1 infection has been associated with high expression of CD38 on peripheral blood (PB) CD81 and CD41 T-cells, which has been related with poor prognosis in untreated HIV-11 patients. In turn, CD38 expression on PB monocytes from HIV-11 individuals and its behavior after starting antiretroviral therapy (ART) have been poorly studied.Methods: CD38 expression on PB CD81 and CD41 T-lymphocytes and monocytes was prospectively analyzed in 30 ART-naive HIV-11 patients, using a quantitative multiparameter flow cytometry approach. Patients were tested prior to therapy, and at weeks 12, 14, 18, 112, and 152 after ART.Results: Prior to ART, CD38 expression was significantly increased on PB CD81 and CD41 T-cells and monocytes; despite a significant decrease after ART, CD38 expression remained abnormally high on PB CD81 T-cells and monocytes, even after one year of therapy, in the absence of detectable plasma viral load. The ART-induced early changes on CD38 expression by PB T-cells and monocytes differed among the cell subsets analyzed and patient groups, probably reflecting an interaction between the direct effects of therapy and a redistribution of the PB compartments of T-cells and monocytes. Hierarchical clustering analysis showed that the overall pattern of changes in CD38 expression observed early after starting ART was predictive of a better response to therapy, not only for PB CD81 T-cells, but also for CD41 T-cells and monocytes. Accordingly, those HIV-11 patients, who experienced a more pronounced increase in CD38 expression on both PB CD41 T-cells and monocytes after 2 weeks of ART, showed a more rapid viral clearance, which might reflect decreased HIV-1 replication in lymph nodes and other tissues, and a partial restoration of hematopoiesis.Conclusions: Combined quantitative measurement of CD38 expression on PB monocytes, and CD81 and CD41 T-cells is a more useful tool for monitoring HIV-11 patients under ART, rather than quantitation of CD38 expression on PB CD81 T-lymphocytes alone. q

Section: Discussionmentioning

confidence: 71%

Relationship between CD38 expression on peripheral blood T‐cells and monocytes, and response to antiretroviral therapy: A one‐year longitudinal study of a cohort of chronically infected ART‐naive HIV‐1+ patients

Cordero

Cytometry Part B Clinical

et al. 2006

“…Before entering the tissues and differentiating into macrophages, monocytes briefly circulate in peripheral blood (28,29). Several studies indicate that circulating monocytes also serve as a viral reservoir in infected individuals (15)(16)(17)33). The infection of circulating monocytes in vivo is at odds with in vitro studies, where monocytes acquire the ability to support productive viral infection only after their differentiation to macrophages (2,4,5,19,20,23,25).…”

mentioning

confidence: 99%

Characterization of Restrictions to Human Immunodeficiency Virus Type 1 Infection of Monocytes

Triques

Stevenson

2004

J Virol

Tissue macrophages are an important cellular reservoir for replication of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus. In vitro, the ability of macrophages to support viral replication is differentiation dependent in that precursor monocytes are refractory to infection. There is, however, no consensus as to the exact point at which infection is restricted in monocytes. We have revisited this issue and have compared the efficiencies of early HIV-1 replication events in monocytes and in differentiated macrophages. Although virus entry in monocytes was comparable to that in differentiated macrophages, synthesis of full-length viral cDNAs was very inefficient. Relative to differentiated macrophages, monocytes contained low levels of dTTP due to low thymidine phosphorylase activity. Exogenous addition of D-thymidine increased dTTP levels to that in differentiated macrophages but did not correct the reverse transcription defect. These results point to a restriction in monocytes that is independent of reverse transcription precursors and suggest that differentiation-dependent cellular cofactors of reverse transcription are rate limiting in monocytes.

The Journal of Immunology

“…Although T lymphocytes are considered to be the major source of latent virus (6), there is a growing body of evidence suggesting that APC can also serve as reservoirs (1,(7)(8)(9)(10). Indeed, because these cells are relatively resistant to cytopathic effects of HIV, they may constitute a major source of persistent infection, particularly in the preterminal stages of AIDS (11,12).…”

mentioning

confidence: 99%

In Vivo CD40-CD154 (CD40 Ligand) Interaction Induces Integrated HIV Expression by APC in an HIV-1-Transgenic Mouse Model

Chougnet

Freitag

Schito

et al. 2001

Because of their relative resistance to viral cytopathic effects, APC can provide an alternative reservoir for latently integrated HIV. We used an HIV-transgenic mouse model in which APC serve as the major source of inducible HIV expression to study mechanisms by which integrated virus can be activated in these cells. When admixed with transgenic APC, activated T lymphocytes provided a major contact-dependent stimulus for viral protein expression in vitro. Using blocking anti-CD154 mAb as well as CD154-deficient T cells, the HIV response induced by activated T lymphocytes was demonstrated to require CD40-CD154 interaction. The role of this pathway in the induction of HIV expression from APC in vivo was further studied in an experimental model involving infection of the HIV-transgenic mice with Plasmodium chabaudi parasites. Enhanced viral production by dendritic cells and macrophages in infected mice was associated with up-regulated CD40 expression. More importantly, in vivo treatment with blocking anti-CD154 mAb markedly reduced viral expression in P. chabaudi-infected animals. Together, these findings indicate that immune activation of integrated HIV can be driven by the costimulatory interaction of activated T cells with APC. Because chronic T cell activation driven by coinfections as well as HIV-1 itself is a characteristic of HIV disease, this pathway may be important in sustaining viral expression from APC reservoirs.