IN VIVO DEPLETION OF CD16+ MONOCYTES IN SIV INFECTED MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Undetectable levels of virus in the plasma of HIV infected patients can be achieved on seemingly effective antiretroviral therapy. However, patients that have terminated treatment, either because of intolerance or noncompliance, experience a rapid resurgence of viral burden, underscoring the role of reservoirs where the virus hide and persist. One such cellular reservoir is monocyte/macrophage lineage cells. Infected monocytes traffic to tissues and become macrophages, which are a major cell type infected in non-lymphoid organs such as the brain, heart and kidney. A subset of blood monocytes expressing the CD16 antigen expands in HIV infected humans and SIV infected macaques, and preferentially harbor virus. It has been hypothesized that the infection and traffic of CD16+ monocytes play a key role in the pathogenesis of neurologic dysfunction associated with HIV infection. For a direct demonstration of their pathogenic role, however, depletion of these cells will be required. Therefore, we originally proposed to use the SIV/macaque model of neuroAIDS (rhesus monkeys that are SIV infected, CD8 lymphocyte depleted) with a depleting anti-CD16 antibody that kills CD16+ monocytes and therefore would block their traffic to tissues. Unfortunately, desirable CD16 monocytes depletion was not achieved with this antibody as we originally expected. And no difference in the outcome of the neurological disorder was observed comparing to the control group. Therefore we decided to take another approach for the next monkey study. It has been recently reported that in SIV macaque models of AIDS, neuroprotective and antiretroviral effects of minocycline, an oral antibiotic, have been demonstrated. Possible neuroprotective mechanisms of minocycline include the inhibition of CD16+ monocytes and/or the reduction of monocyte turnover and traffic, as suggested in other studies. Through the in vivo modulation of monocyte responses during SIV infection, we will evaluate more precisely, in a prospective manner, the role of increased monocyte turnover and CD16+ monocytes, and also be able to determined whether the decreased monocyte turnover will have any effect of AIDS progression. Oral minocycline, a widely used generic antibiotic with a good safety record in humans and animals, has been tested extensively in many experimental animals including monkeys. No adverse effects or side effects at the tested doses were observed even following chronic daily administration in macaques (60 days). The daily dose we propose to administer orally is the usual (low) clinical dose of intravenous minocycline. Overall, no adverse effects are anticipated from the treatment.