HIV and CD16+ monocytes as cellular reservoir & HIV/pulmonary hypertension

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The dynamics of viral replication and evolution in the lungs of patients infected with Human Immunodeficiency Virus type-1 (HIV-1) remain poorly understood. In addition, pulmonary complications are still prevalent despite the unquestioned success of Highly Active Antiretroviral Therapy (HAART). HIV-1 replicates extensively during the acute phase of infection in peripheral blood and end organs. After seroconversion, and suppression of HIV viral loads by HAART, patients may undergo a phase of sub-clinical viremia (HIV residual replication). This phase refers to a stage in which the virus replicates below the levels of detection. During this phase, tissues may be reseeded with quasispecies that are not necessarily detected in the peripheral plasma. Several anatomical sites provide HIV with protected compartments for viral replication and evolution; these may be important sources for the sub-clinical viremia. These compartments include the brain, gut-associated lymphoid tissue, bone marrow, and genital tract, etc. Research efforts are now focused on the search for cellular reservoirs other than lymphocytes during the residual replication of HIV. Evidence points to myeloid cells as the cellular reservoirs of virus not reseeded from plasma viruses. HIV+ patients are more frequently diagnosed with HIV-related pulmonary hypertension (HRPAH) compared to the general population, regardless of suppressive HAART. HRPAH is a disease with a prominent inflammatory component that is also linked to higher mortality. Our group has demonstrated that HIV Nef is associated with vascular remodeling and lumen- obliterative PAH-like lesions in the lungs of SHIV-nef-infected macaques. Of note, these lesions appeared only in the lungs (not in other organs) and were preceded by inflammatory infiltrates. Others have also shown that HIV Envelope (Env) glycoprotein 120 induces vascular remodeling as well. Furthermore, we have evidence that patients diagnosed with bona fide HRPAH harbor specific nef alleles in the peripheral blood. Whether HRPAH patients harbor only a signature Nef or signature HIV quasispecies with genes like env evolving in concert remains unknown at this time. The cellular sources of HIV and their impact in the lung vasculature of HRPAH patients receiving suppressive HAART also remain to be elucidated. The applicant and others have shown that classic CD14+ monocytes do not carry HIV during suppressive HAART and CD16+ pro- inflammatory monocytes in peripheral blood harbor viral quasispecies different from those in plasma of viremic patients. Peripheral blood CD16+ monocytes resemble alveolar macrophages, and undergo transendothelial migration when infected with HIV. Given these intriguing observations, we think that HRPAH patients HRPAH- associated quasispecies. Peripheral blood CD16+ monocytes in HIV-infected patients serve as Trojan horses for these specific HIV quasispecies. After reaching the lung and upon activation, these pro-inflammatory lung monocyte/macrophages reseed the lung with such virions, starting a vicious cycle in which encoded Nef and Env increase the production of inflammatory molecules that may impact endothelial cells. Subsequently, injured endothelial cells may switch to a proliferative-angiogenic phenotype leading to the clinical picture of HRPAH. We will use several laboratory techniques single-genome amplification, phylogenetic analyses, cell isolation using magnetic beads, fluorescent in itu hybridization and in vivo cell imaging.