Recovery of Replication-Competent HIV Type 1-Infected Circulating Monocytes from Individuals Receiving Antiretroviral Therapy

Abstract

The affect of antiretroviral therapy (ART) on HIV-1 recovery from blood monocytes was determined in purified peripheral blood monocyte-derived macrophage (MDM) cultures from HIV-1-infected subjects with undetectable plasma viremia or active viral replication. Additionally, the association between replication-competent HIV-1-infected MDM and neurocognitive status was examined. Fifty-two individual with previous AIDS-defining illnesses receiving nucleoside analogues with and without protease inhibitors or no ART were followed for up to 1.5 years. Detection of plasma viremia significantly correlated with the occurrence of infected monocytes. Viral replication was detected in less than 10% of the MDM cultures from 23 individuals receiving effective antiretroviral therapy. In contrast, approximately 50% of the MDM cultures from 29 individuals with active viral replication and evidence of decreased immune function, including all individuals with neurocognitive impairment, produced detectable virus indicating that a lack of adequate ART results in increased abundance of replication-competent blood monocytes. Proviral DNA levels were a minimum of 13-fold higher in MDM from subjects with active viral replication. The infrequent detection of viral DNA in cultures from individuals receiving effective ART suggested low levels of circulating monocytes harboring replication-incompetent virus. These studies demonstrate that HIV-infected individuals on ART with breakthrough viremia have significantly higher levels of circulating infected monocytes, the precursors of tissue macrophages.

HIV-1 decreases Nrf2/ARE activity and phagocytic function in alveolar macrophages

“…Clinical data have shown that despite an HIV-1 viral load below the limit of detection in patients with HIV/AIDS treated with ART, HIV-1 infected Mfs are found in the tissues, and proviral DNA can be detected in Mfs [5,25]. Importantly, susceptibility to infection in individuals with HIV-1/AIDS is likely a consequence of defective AM innate immune functions, including phagocytosis, intracellular killing, and inflammatory cytokine production [24,26].…”

Immune Suppression by Myeloid Cells in HIV Infection: New Targets for Immunotherapy

“…They are able to cross the blood-tissue barriers and can transfer HIV to all tissues and organs. It has also been reported that the macrophages isolated from patients receiving ART harbour replication competent HIV [ 72 ]. These findings indicate that the infected macrophage, are of critical importance in HIV pathogenesis contributing to early-stage cell-to-cell viral transmission, dissemination and persistence throughout the body.…”

“…Monocytes are targets of HIV infection as they express the CD4 receptor and chemokine co-receptors for HIV entry. However, both in vivo and in vitro data suggest infection of circulating monocytes with HIV to be rare in comparison to CD4 T cell compartments [ 72 - 74 ], which is often latent and could lead to productive infection during differentiation into macrophages. Later on, sophisticated approaches using in situ hybridization coupled with simultaneous surface immuno-phenotyping revealed a higher level of monocyte infection and demonstrated the production of viral mRNA in these cells indicating productive infection [ 75 , 76 ].…”

Changing Patterns in the Neuropathogenesis of HIV During the HAART Era

“…A study on the effect of HAART on HIV-1 recovery from purified peripheral blood monocyte-derived macrophages showed that circulating monocytes constitute a significant source of replication-competent virus in HAART naive HIV patients and in HIV patients failing HAART (44). Moreover, a study by Lanier et al describing evolutionary relationships between the HIV-1 reverse transcriptase from multiple anatomical compartments of a patient enrolled in a phase III trial designed to assess the efficacy of ABC in subjects with HAD, reports compartmentalized evolution in the midfrontal gyrus of the brain and suggest that incomplete drug penetrance into this region may in part be responsible (47,65).…”