This review provides recent information relating to how monocytes and macrophages contribute to persistence of HIV-1 in individuals with highly active antiretroviral therapy-induced viral suppression.

The restriction factor APOBEC-3G after entry is present in an active form in monocytes but not macrophages, providing an explanation for why monocytes are less susceptible to HIV-1 infection than macrophages. A subset of monocytes is, however, more susceptible to HIV-1 infection than the majority of blood monocytes. New techniques allow distinction between stably integrated and unintegrated forms of HIV DNA, resulting in demonstration that rebounding HIV-1 is genetically distinct to virus in the T-cell latent reservoir. Controversy has ended by showing that extrachromosomal 2-LTR circles are stable in terminally differentiated monocytes/macrophages but represent ongoing viral replication in proliferating cells. Infectious virions are present in cytoplasmic compartments for prolonged periods of time, thus supporting the role of these cells as a source of viral persistence. Whilst the intestinal macrophage is not likely to provide a source of viral persistence, residual infection can be detected in the genital tract and brain macrophages in individuals on highly active antiretroviral therapy. Antiretroviral drug resistance may emerge more slowly in monocytes/macrophages than in T cells, as recently demonstrated for lamivudine.

Although many questions are still unanswered, there is increasing recognition that latent T-cell reservoirs cannot fully explain the failure of highly active antiretroviral therapy to eradicate HIV-1 and that monocytes/macrophages play a critical role as a source of residual infection.