New Reservoir for Persistent HIV Infection Identified

Persistence of HIV infection in macrophages in various parts of the body is a major stumbling block in achieving a cure and should be addressed according to a team of scientists at the Division of Infectious Diseases at the University of North Carolina (UNC) School of Medicine.

Reason for the Study

HIV infection is a major public health concern worldwide. There is no cure or vaccine in sight though various treatments such as antiretroviral therapy (ART) that reduce viral multiplication and transmission are available that allow infected persons to lead productive lives. However, persistence of the virus in reservoirs such as macrophages is a major barrier to achieving eradication of the infection and to prevent its spread to other sites within the body.

In an study led by J. Victor Garcia, Ph. D., professor of medicine, microbiology and immunology at UNC School of Medicine, he demonstrated that tissue macrophages could support HIV replication in vivo even if there were no human T-cells.

However, whether these macrophages responded to ART and whether they represented a potential reservoir of infection even after ART treatment was not still clear. The current study aimed to find out the answer and to carry the research forwards.

Methods and Findings of the Study

Employing a humanized myeloid only mouse model carrying functioning human genes and cells but totally devoid of T-cells, the research team were able to show the following.

• HIV infection in tissue macrophages responded to ART.
• Following suspension of ART, there was rapid reactivation of infection in about 1/3^rd of the animals, which corresponded to establishment of persistent infection in tissue macrophages.

“This is the first report demonstrating that tissue macrophages can be infected and that they respond to antiretroviral therapy," Jenna Honeycutt the lead author and postdoctoral research associate in the UNC Division of Infectious Diseases said. "In addition, we have shown that productively infected macrophages can persist despite ART; and most importantly, that they can reinitiate and sustain infection upon therapy interruption even in the absence of T cells - the major target of HIV infection.”

Role of Macrophages in HIV Infection

Macrophages are cells of the white cell lineage; in blood they occur as monocytes and in tissues they get modified to form macrophages, an important cell of the immune system. They occur in a wide variety of tissues such as the lung, liver, brain and bone marrow.

• Macrophages in the brain and lung can survive for several weeks to years and thus macrophages infected by HIV serve as a major reservoir of infection contributing to reactivation of infection and inability of current therapies to eliminate the virus completely.
• They can disseminate to virtually all organs within the body and contribute to spread of infection within the patient.
• Macrophages have been shown to be critical in mother to child transmission of infection via breastfeeding.

These observations strengthen the fact that any future therapeutic intervention to eradicate HIV might need to target two very different types of cells, namely the T-cells and the macrophages.

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Plans For Future Research

In the future, the research team hopes to elucidate the following:

• Factors favoring persistent HIV infection in macrophages.
• Sites in the body where persistently infected macrophages can occur.
• Response of macrophages to possible forms of treatment aimed at eliminating HIV infection from the body.

Status of Current HIV Treatment and Research Trends

• Currently, the major limiting factor in HIV treatment is the inability to address viral reservoirs and toxicities plus the cost of treatment that could cause patients to default on treatment.
• Attempts to eradicate viral reservoirs have been bone marrow transplantation and gene therapy in the presence of anti-HIV therapy.
• Initiation of ART early during acute phase of the infection can restrict the formation or the size of the viral reservoir and provide a functional cure.
• Efforts to develop effective vaccines and alternative strategies to achieve HIV cure are being pursued diligently.

References:

1. Cellular Reservoirs of HIV-1 and their Role in Viral Persistence - (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2683678/)
2. Current Trends in HIV/AIDS - (http://jscholaronline.org/full-text/JAID/102/Current-trends-in-hiv-aids.php)

Source-Medindia