CNS-specific regulatory elements in brain-derived HIV-1 strains affect responses to latency-reversing agents with implications for cure strategies.

Latency-reversing agents (LRAs), including histone deacetylase inhibitors (HDACi), are being investigated as a strategy to eliminate latency in HIV-infected patients on suppressive antiretroviral therapy. The effectiveness of LRAs in activating latent infection in HIV strains derived from the central nervous system (CNS) is unknown. Here we show that CNS-derived HIV-1 strains possess polymorphisms within and surrounding the Sp transcription factor motifs in the long terminal repeat (LTR). These polymorphisms result in decreased ability of the transcription factor specificity protein 1 to bind CNS-derived LTRs, reducing the transcriptional activity of CNS-derived viruses. These mutations result in CNS-derived viruses being less responsive to activation by the HDACi panobinostat and romidepsin compared with lymphoid-derived viruses from the same subjects. Our findings suggest that HIV-1 strains residing in the CNS have unique transcriptional regulatory mechanisms, which impact the regulation of latency, the consideration of which is essential for the development of HIV-1 eradication strategies.

HIV eradication symposium: will the brain be left behind?

On 18 July 2014, the National Institute of Mental Health in collaboration with ViiV Health Care and Boehringer Ingelheim supported a symposium on HIV eradication and what it meant for the brain. The symposium was an affiliated event to the 20th International AIDS Conference. The meeting was held in Melbourne, Australia, and brought together investigators currently working on HIV eradication together with investigators who are working on the neurological complications of HIV. The purpose of the meeting was to bring the two fields of HIV eradication and HIV neurology together to foster dialogue and cross talk to move the eradication field forward in the context of issues relating to the brain as a potential reservoir of HIV. The outcomes of the symposium were that there was substantive but not definitive evidence for the brain as an HIV reservoir that will provide a challenge to HIV eradication. Secondly, the brain as a clinically significant reservoir for HIV is not necessarily present in all patients. Consequently, there is an urgent need for the development of biomarkers to identify and quantify the HIV reservoir in the brain. Lastly, when designing and developing eradication strategies, it is critical that approaches to target the brain reservoir be included.

Human immunodeficiency virus type 1 stimulates the expression and production of secretory leukocyte protease inhibitor (SLPI) in oral epithelial cells: a role for SLPI in innate mucosal immunity.

The innate immune response is a key barrier against pathogenic microorganisms such as human immunodeficiency virus type 1 (HIV-1). Because HIV-1 is rarely transmitted orally, we hypothesized that oral epithelial cells participate in the innate immune defense against this virus. We further hypothesized that secretory leukocyte protease inhibitor (SLPI), a 12-kDa mucosal antiviral protein, is a component of the host immune response to this virus. Here we demonstrated constitutive expression and production of SLPI in immortalized human oral keratinocytes. Brief exposure of cells to HIV-1 BaL and HXB2 significantly increased SLPI mRNA and protein production compared to that in mock-exposed cells (P < 0.01), as evaluated by real-time quantitative reverse transcription-PCR and enzyme-linked immunosorbent assay. HIV-1-mediated stimulation of SLPI occurred at the transcriptional level, was dose and time dependent, was elicited by heat-inactivated and infectious viruses, and did not depend on cellular infection. Experiments with purified retroviral proteins showed that the stimulatory effect was induced specifically by external envelope glycoproteins from HIV-1 and simian immunodeficiency virus. SLPI responsiveness to HIV-1 was also observed in an unrelated oral epithelial cell line and in normal (nonimmortalized) human oral epithelial cells isolated from healthy uninfected gingival tissues. In this first report of SLPI regulation by HIV-1, we show that the expression and production of the antimicrobial and anti-inflammatory protein can be stimulated in oral epithelial cells by the virus through interactions with gp120 in the absence of direct infection. These findings indicate that SLPI is a component of the oral mucosal response to HIV-1.

Hyper-excretion of human immunodeficiency virus type 1 RNA in saliva.

Anatomical compartments (e.g., the reproductive tract) are reservoirs of human immunodeficiency virus type-1 (HIV-1) and potential sites of residual infection in patients receiving anti-retroviral therapy (ART). Viral hyper-excretion relative to blood is a hallmark of reservoirs. To determine whether hyper-excretion can occur in the oral cavity, we compared viral loads in blood plasma and saliva of 67 adults. Salivary viral hyperexcretion was defined as a four-fold or higher viral load in saliva than in plasma. HIV-1 RNA was detected in 79% of plasma samples, in 44% of unfiltered saliva samples, in 16% of filtered saliva samples, and in 59% of saliva-derived cell pellets. Compared with non-hyper-excretors (n = 62), hyper-excretors (n = 5) had elevated levels of viral RNA in unfiltered saliva and saliva-derived cells, HIV-associated periodontal disease, gingival inflammation, and no combination ART. Morphological characterization of cell pellets identified lymphocytes as a likely HIV-1 source. These collective findings are consistent with an oral HIV-1 reservoir in selected individuals.