Dataset Information

Early Sites of Virus Replication After Oral SIVmac251 Infection of Infant Macaques: Implications for Pathogenesis.

ABSTRACT: Despite optimization of preventative measures for vertical HIV-1 transmission, daily, roughly 400 infants become HIV infected, most of them through breastfeeding. Viral entry has been presumed to occur in the gastrointestinal tract; however, the exact entry site(s) have not been defined. Therefore, we quantified simian immunodeficiency virus (SIV) RNA and DNA in oral, intestinal, and systemic tissues of 15 infant macaques within 48-96?h after oral SIVmac251 exposure. SIV DNA was detected as early as 48?h, whereas SIV RNA was typically detected at later time points (72-96?h). Transmitted founder viruses were identical or very similar to a single genotype in the SIVmac251 challenge stock. SIV RNA and DNA were most frequently found in lymph nodes (LNs) draining the oral cavity and in the ileum. Using in situ hybridization, SIV-infected cells in LNs were exclusively represented by CD3+ T cells. SIV RNA and DNA were also detected in the lungs of 20% of the animals, and 60% of the animals had detectable SIV DNA in the cerebrum. The early detection of viral RNA or DNA in lung and brain tissues emphasizes the need for early treatment of pediatric HIV infection to prevent damage not only to the immune system but also to the respiratory tract and central nervous system.

SUBMITTER: Amedee AM

PROVIDER: S-EPMC5863100 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Early Sites of Virus Replication After Oral SIV<sub>mac251</sub> Infection of Infant Macaques: Implications for Pathogenesis.

Amedee Angela M AM Phillips Bonnie B Jensen Kara K Robichaux Spencer S Lacour Nedra N Burke Mark M Piatak Michael M Lifson Jeffrey D JD Kozlowski Pamela A PA Van Rompay Koen K A KKA De Paris Kristina K

AIDS research and human retroviruses 20180117 3

Despite optimization of preventative measures for vertical HIV-1 transmission, daily, roughly 400 infants become HIV infected, most of them through breastfeeding. Viral entry has been presumed to occur in the gastrointestinal tract; however, the exact entry site(s) have not been defined. Therefore, we quantified simian immunodeficiency virus (SIV) RNA and DNA in oral, intestinal, and systemic tissues of 15 infant macaques within 48-96 h after oral SIV<sub>mac251</sub> exposure. SIV DNA was detec ...[more]

PMID: 29237287

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Project description:BACKGROUND: Extensive studies of primary infection are crucial to our understanding of the course of HIV disease. In SIV-infected macaques, a model closely mimicking HIV pathogenesis, we used a combination of three markers -- viral RNA, 2LTR circles and viral DNA -- to evaluate viral replication and dissemination simultaneously in blood, secondary lymphoid tissues, and the gut during primary and chronic infections. Subsequent viral compartmentalization in the main target cells of the virus in peripheral blood during the chronic phase of infection was evaluated by cell sorting and viral quantification with the three markers studied. RESULTS: The evolutions of viral RNA, 2LTR circles and DNA levels were correlated in a given tissue during primary and early chronic infection. The decrease in plasma viral load principally reflects a large decrease in viral replication in gut-associated lymphoid tissue (GALT), with viral RNA and DNA levels remaining stable in the spleen and peripheral lymph nodes. Later, during chronic infection, a progressive depletion of central memory CD4+ T cells from the peripheral blood was observed, accompanied by high levels of viral replication in the cells of this subtype. The virus was also found to replicate at this point in the infection in naive CD4+ T cells. Viral RNA was frequently detected in monocytes, but no SIV replication appeared to occur in these cells, as no viral DNA or 2LTR circles were detected. CONCLUSION: We demonstrated the persistence of viral replication and dissemination, mostly in secondary lymphoid tissues, during primary and early chronic infection. During chronic infection, the central memory CD4+ T cells were the major site of viral replication in peripheral blood, but viral replication also occurred in naive CD4+ T cells. The role of monocytes seemed to be limited to carrying the virus as a cargo because there was an observed lack of replication in these cells. These data may have important implications for the targeting of HIV treatment to these diverse compartments.

Project description:Feline immunodeficiency virus (FIV) is the feline analogue of human immunodeficiency virus (HIV) and features many hallmarks of HIV infection and pathogenesis, including the development of concurrent oral lesions. While HIV is typically transmitted via parenteral transmucosal contact, recent studies prove that oral transmission can occur, and that saliva from infected individuals contains significant amounts of HIV RNA and DNA. While it is accepted that FIV is primarily transmitted by biting, few studies have evaluated FIV oral infection kinetics and transmission mechanisms over the last 20 years. Modern quantitative analyses applied to natural FIV oral infection could significantly further our understanding of lentiviral oral disease and transmission. We therefore characterized FIV salivary viral kinetics and antibody secretions to more fully document oral viral pathogenesis. Our results demonstrate that: (i) saliva of FIV-infected cats contains infectious virus particles, FIV viral RNA at levels equivalent to circulation, and lower but significant amounts of FIV proviral DNA; (ii) the ratio of FIV RNA to DNA is significantly higher in saliva than in circulation; (iii) FIV viral load in oral lymphoid tissues (tonsil, lymph nodes) is significantly higher than mucosal tissues (buccal mucosa, salivary gland, tongue); (iv) salivary IgG antibodies increase significantly over time in FIV-infected cats, while salivary IgA levels remain static; and, (v) saliva from naïve Specific Pathogen Free cats inhibits FIV growth in vitro. Collectively, these results suggest that oral lymphoid tissues serve as a site for enhanced FIV replication, resulting in accumulation of FIV particles and FIV-infected cells in saliva. Failure to induce a virus-specific oral mucosal antibody response, and/or viral capability to overcome inhibitory components in saliva may perpetuate chronic oral cavity infection. Based upon these findings, we propose a model of oral FIV pathogenesis and suggest alternative diagnostic modalities and translational approaches to study oral HIV infection.

Dataset Information

Early Sites of Virus Replication After Oral SIVmac251 Infection of Infant Macaques: Implications for Pathogenesis.

Publications

Early Sites of Virus Replication After Oral SIV<sub>mac251</sub> Infection of Infant Macaques: Implications for Pathogenesis.

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