It is known that HIV, the causative agent of AIDS, is severely species restricted, and, to date, only humans and chimpanzees have been shown to be susceptible to infection. Human infection by HIV is restricted to cells expressing the CD4 molecule. In addition to CD4, productive HIV infection requires one of two different G protein–coupled receptors, namely CCR5 or CXCR4. However, despite the prevalence of virus in CD4+ T cells, it is clear that T cells are not the only targets and initial hosts of HIV infection. Now, a study from researchers at the University of North Carolina has shown that HIV infects and reproduces in macrophages, large white blood cells found in the liver, brain and connective tissues of the body. The team state that their data shows macrophages represent a genuine target for HIV infection, can sustain and transmit infection, as well as having implications for cure research. The opensource study is published in the Journal of Clinical Investigation.
Previous studies show that macrophages are myeloid lineage cells which ingest foreign material, including HIV-infected CD4 T cells. Past studies concluded macrophages became infected upon ingestion of compromised CD4 T cells. In fact, macrophages have recently been shown to express CD4, CCR5, and CXCR4 and to be susceptible to HIV and SIV infection in vitro and in vivo. Whereas the ability of HIV to replicate in human macrophages in vitro has been extensively documented, evidence for HIV replication in human macrophages in vivo is limited and, in some instances, indirect. This is because analysis of primary tissue macrophages from humans remains difficult, as these samples are not easily accessible. To overcome this the current study developed a transgenic myeloid-only mouse model to investigate if tissue macrophages are productively infected with HIV.
The current study shows that macrophages can sustain HIV replication in the absence of T cells. Results show that HIV-infected macrophages are distributed in various tissues including the brain. Data findings show that the replication-competent virus can be rescued from infected macrophages obtained from tissues of the transgenic myeloid-only mouse model and the infected macrophages can then establish infection in new hosts.
The lab state that by studying HIV in novel small animal models that have no T cells, the cells that easily support HIV infection, they found HIV- infected macrophages, proving macrophage-tropic strains of HIV exist and can autonomously replicate in these important cells. They go on to add now the global medical community know that HIV targets macrophages and that the virus replicates there, the next step will be to introduce antiretroviral therapy into the models to see if the virus continues to replicate despite treatment. The group conclude that their study unequivocally demonstrates macrophages are a clear source of the replicating HIV virus.
The team surmise that their model will allow the global medical community to ask the critical question as to whether or not macrophages represent a latent reservoir for HIV after treatment with antiretroviral therapy. For the future, the researchers state that these experiments will inform the direction of HIV cure research.