Acute SIV Infection in Sooty Mangabey Monkeys Is Characterized by Rapid Virus Clearance from Lymph Nodes and Absence of Productive Infection in Germinal Centers

Lymphoid tissue immunopathology is a characteristic feature of chronic HIV/SIV infection in AIDS-susceptible species, but is absent in SIV-infected natural hosts. To investigate factors contributing to this difference, we compared germinal center development and SIV RNA distribution in peripheral lymph nodes during primary SIV infection of the natural host sooty mangabey and the non-natural host pig-tailed macaque. Although SIV-infected cells were detected in the lymph node of both species at two weeks post infection, they were confined to the lymph node paracortex in immune-competent mangabeys but were seen in both the paracortex and the germinal center of SIV-infected macaques. By six weeks post infection, SIV-infected cells were no longer detected in the lymph node of sooty mangabeys. The difference in localization and rate of disappearance of SIV-infected cells between the two species was associated with trapping of cell-free virus on follicular dendritic cells and higher numbers of germinal center CD4+ T lymphocytes in macaques post SIV infection. Our data suggests that fundamental differences in the germinal center microenvironment prevent productive SIV infection within the lymph node germinal centers of natural hosts contributing to sustained immune competency

TRIM5 Suppresses Cross-Species Transmission of a Primate Immunodeficiency Virus and Selects for Emergence of Resistant Variants in the New Species

Cross-species transmission of simian immunodeficiency virus from sooty mangabeys (SIVsm) into rhesus macaques, and subsequent emergence of pathogenic SIVmac, required adaptation to overcome restriction encoded by the macaque TRIM5 gene

Differential CD4+ T-Lymphocyte Apoptosis and Bystander T-Cell Activation in Rhesus Macaques and Sooty Mangabeys during Acute Simian Immunodeficiency Virus Infection▿

In contrast to pathogenic lentiviral infections, chronic simian immunodeficiency virus (SIV) infection in its natural host is characterized by a lack of increased immune activation and apoptosis. To determine whether these differences are species specific and predicted by the early host response to SIV in primary infection, we longitudinally examined T-lymphocyte apoptosis, immune activation, and the SIV-specific cellular immune response in experimentally infected rhesus macaques (RM) and sooty mangabeys (SM) with controlled or uncontrolled SIV infection. SIVsmE041, a primary SIVsm isolate, reproduced set-point viremia levels of natural SIV infection in SM but was controlled in RM, while SIVmac239 replicated to high levels in RM. Following SIV infection, increased CD8+ T-lymphocyte apoptosis, temporally coinciding with onset of SIV-specific cellular immunity, and elevated plasma Th1 cytokine and gamma interferon-induced chemokine levels were common to both SM and RM. Different from SM, SIV-infected RM showed a significantly higher frequency of peripheral blood activated CD8+ T lymphocytes despite comparable magnitude of the SIV-specific gamma interferon enzyme-linked immunospot response. Furthermore, an increase in CD4+ and CD4−CD8− T-lymphocyte apoptosis and plasma tumor necrosis factor-related apoptosis-inducing ligand were observed only in RM and occurred in both controlled SIVsmE041 and uncontrolled SIVmac239 infection. These data suggest that the “excess” activated T lymphocytes in RM soon after SIV infection are predominantly of non-virus-specific bystander origin. Thus, species-specific differences in the early innate immune response appear to be an important factor contributing to differential immune activation in natural and nonnatural hosts of SIV infection

Immunohistochemistry for CD4, CD8, and IBA-1 in GC of SM and PM.

*<p>indicate accompanying image in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057785#pone-0057785-g004" target="_blank">Fig. 4</a>.</p><p>Mean score for DAB staining at each time point post-SIV inoculation. PM have higher CD4 scores at 2, 5, and 21 wpi compared to SM at similar time-points. PM also had slightly increased numbers of IBA-1⁺ cells (macrophages) at 2 wpi compared to SM. CD8 scores are slightly higher for PM at 5 and 21 wpi. Overall number of CD8⁺ cells in GC of both species is extremely low. Asterisks indicate accompanying image in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0057785#pone-0057785-g004" target="_blank">Figure 4A</a>.</p

Localization of SIV infected cells in LN from SM and PM.

<p>Infected cells, as quantified by ISH for SIV RNA. Histomorphological localization of infected cells (identified by dark blue NBT/BCIP chromogen) in GC versus paracortical microenvironments was accomplished by microscopic analysis of Nuclear Fast Red counterstain. Scoring is based on the average for each group at each time point, divided into quartiles (+; 0–5/mm²) (++; 6–15/mm²); (+++; 16–50/mm²); (++++; >50/mm²) derived from quantitative measurements. Asterisk (*) Indicates one germinal center contained an SIV-infected cell at 2, 6, and 24 wpi in a CD8 depleted SM. Numbers of GC evaluated at each time-point is indicated by n values.</p