CCL2: a Chemokine Potentially Promoting Early Seeding of the Latent HIV Reservoir
Thomas A. Packard,
Roland Schwarzer,
Eytan Herzig,
Deepashri Rao,
Xiaoyu Luo,
Johanne H. Egedal,
Feng Hsiao,
Marek Widera,
Judd F. Hultquist,
Zachary W. Grimmett,
Ronald J. Messer,
Nevan J. Krogan,
Steven G. Deeks,
Nadia R. Roan,
Ulf Dittmer,
Kim J. Hasenkrug,
Warner C. Greene
Affiliations
Thomas A. Packard
J. David Gladstone Institutes, San Francisco, California, USA
Roland Schwarzer
J. David Gladstone Institutes, San Francisco, California, USA
Eytan Herzig
J. David Gladstone Institutes, San Francisco, California, USA
Deepashri Rao
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Xiaoyu Luo
J. David Gladstone Institutes, San Francisco, California, USA
Johanne H. Egedal
J. David Gladstone Institutes, San Francisco, California, USA
Feng Hsiao
J. David Gladstone Institutes, San Francisco, California, USA
Marek Widera
Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Judd F. Hultquist
J. David Gladstone Institutes, San Francisco, California, USA
Zachary W. Grimmett
J. David Gladstone Institutes, San Francisco, California, USA
Ronald J. Messer
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Nevan J. Krogan
J. David Gladstone Institutes, San Francisco, California, USA
Steven G. Deeks
Department of Medicine, University of California San Francisco, San Francisco, California, USA
Nadia R. Roan
J. David Gladstone Institutes, San Francisco, California, USA
Ulf Dittmer
Institute for Translational HIV Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Kim J. Hasenkrug
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA
Warner C. Greene
J. David Gladstone Institutes, San Francisco, California, USA
ABSTRACT HIV infects long-lived CD4 memory T cells, establishing a latent viral reservoir that necessitates lifelong antiretroviral therapy (ART). How this reservoir is formed so quickly after infection remains unclear. We now show the innate inflammatory response to HIV infection results in CCL2 chemokine release, leading to recruitment of cells expressing the CCR2 receptor, including a subset of central memory CD4 T cells. Supporting a role for the CCL2/CCR2 axis in rapid reservoir formation, we find (i) treatment of humanized mice with anti-CCL2 antibodies during early HIV infection decreases reservoir seeding and preserves CCR2/5+ cells and (ii) CCR2/5+ cells from the blood of HIV-infected individuals on long-term ART contain significantly more integrated provirus than CCR2/5-negative memory or naive cells. Together, these studies support a model where the host’s innate inflammatory response to HIV infection, including CCL2 production, leads to the recruitment of CCR2/5+ central memory CD4 T cells to zones of virus-associated inflammation, likely contributing to rapid formation of the latent HIV reservoir. IMPORTANCE There are currently over 35 million people living with HIV worldwide, and we still have no vaccine or scalable cure. One of the difficulties with HIV is its ability to rapidly establish a viral reservoir in lymphoid tissues that allows it to elude antivirals and the immune system. Thus, it is important to understand how HIV accomplishes this so we can develop preventive strategies. Our current results show that an early inflammatory response to HIV infection includes production of the chemokine CCL2, which recruits a unique subset of CCR2/5+ CD4+ T cells that become infected and form a significant reservoir for latent infection. Furthermore, we show that blockade of CCL2 in humanized mice significantly reduces persistent HIV infection. This information is relevant to the development of therapeutics to prevent and/or treat chronic HIV infections.
