Simian immunodeficiency virus (SIV)-infected African nonhuman primates do not progress to AIDS in spite of high and persistent viral loads (VLs). Some authors consider the high viral replication observed in chronic natural SIV infections to be due to lower anti-SIV antibody titers than those in rhesus macaques, suggesting a role of antibodies in controlling viral replication. We therefore investigated the impact of antibody responses on the outcome of acute and chronic SIVagm replication in African green monkeys (AGMs). Nine AGMs were infected with SIVagm.sab. Four AGMs were infused with 50 mg/kg of body weight anti-CD20 (rituximab; a gift from Genentech) every 21 days, starting from day ؊7 postinfection up to 184 days. The remaining AGMs were used as controls and received SIVagm only. Rituximab-treated AGMs were successfully depleted of CD20 cells in peripheral blood, lymph nodes (LNs), and intestine, as shown by the dynamics of CD20 ؉ and CD79a ؉ cells. There was no significant difference in VLs between CD20-depleted AGMs and control monkeys: peak VLs ranged from 10 7 to 10 8 copies/ml; set-point values were 10 4 to 10 5 SIV RNA copies/ml. Levels of acute mucosal CD4 ؉ T-cell depletion were similar for treated and nontreated animals. SIVagm seroconversion was delayed for the CD20-depleted AGMs compared to results for the controls. There was a significant difference in both the timing and magnitude of neutralizing antibody responses for CD20-depleted AGMs compared to results for controls. CD20 depletion significantly altered the histological structure of the germinal centers in the LNs and Peyer's patches. Our results, although obtained with a limited number of animals, suggest that humoral immune responses play only a minor role in the control of SIV viral replication during acute and chronic SIV infection in natural hosts.

While simian immunodeficiency viruses (SIVs) are generally nonpathogenic in their natural hosts, dramatic increases in pathogenicity may occur upon cross-species transmission to new hosts. Deciphering the drivers of these increases in virulence is of major interest for understanding the emergence of new human immunodeficiency viruses (HIVs). We transmitted SIVsab from the sabaeus species of African green monkeys (AGMs) to pigtailed macaques (PTMs). High acute viral replication occurred in all SIVsab-infected PTMs, yet the outcome of chronic infection was highly variable, ranging from rapid progression to controlled infection, which was independent of the dynamics of acute viral replication, CD4؉ T cell depletion, or preinfection levels of microbial translocation. Infection of seven PTMs with plasma collected at necropsy from a rapid-progressor PTM was consistently highly pathogenic, with high acute and chronic viral replication, massive depletion of memory CD4 ؉ T cells, and disease progression in all PTMs. The plasma inoculum used for the serial passage did not contain adventitious bacterial or viral contaminants. Single-genome amplification showed that this inoculum was significantly more homogenous than the inoculum directly derived from AGMs, pointing to a strain selection in PTMs. In spite of similar peak plasma viral loads between the monkeys in the two passages, immune activation/inflammation levels dramatically increased in PTMs infected with the passaged virus. These results suggest that strain selection and a massive cytokine storm are major factors behind increased pathogenicity of SIV upon serial passage and adaptation of SIVs to new hosts following cross-species transmission. IMPORTANCEWe report here that upon cross-species transmission and serial passage of SIVsab from its natural host, the sabaeus African green monkey (AGM), to a new host, the pigtailed macaque (PTM), viral adaptation and increased pathogenicity involve strain selection and a massive cytokine storm. These results permit the design of strategies aimed at preventing cross-species transmission from natural hosts of SIVs to humans in areas of endemicity. Furthermore, our study describes a new animal model for SIV infection. As the outcomes of SIVsab infection in PTMs, African green monkeys, and rhesus macaques are different, the use of these systems enables comparative studies between pathogenic, nonpathogenic, and elite-controlled infections, to gain insight into the mechanisms of SIV immunodeficiency and comorbidities.

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Background: It is unclear whether a connection exists between femoral head size, offset, neck length, and cup abduction angles, and rate of revision in metal-on-metal (MoM) total hip arthroplasty (THA) implant systems. Methods: A retrospective review of MoM THA completed by a single surgeon with a single implant between 2003 and 2008 was conducted. Patient demographics, implant data, radiographs, and revision details were collected at follow-up. Incidence rates for revision and osteolysis were calculated in regard to the femoral head size, stem offset, neck length, and cup abduction angles. Results: Six hundred and ninety two THAs were identified, with 79% of patients returning for a median follow-up of 10.3 years (interquartile range ¼ 6.0-12.3). The median time to revision was 7.5 years (interquartile range ¼ 5.3-9.9) among 27 total revision surgeries. The overall incidence rate of revision was 5.4 revisions per 1000 person-years, 3.0 revisions per 1000 person-years for adverse local tissue reaction. Hips with a cup abduction angle of 40 had revisions at nearly twice the rate of those with an angle of 41-50 (incidence rate ratio ¼ 1.98, 95% confidence interval: 0.92, 4.29). Hips with a 9 mm neck length had an increased rate of revision (incidence rate ratio ¼ 5.94, 95% confidence interval: 1.33, 26.55) relative to those with a neck length of 0 mm. Rates of osteolysis were similar between implants of different head sizes, neck lengths and cup abduction angles. Conclusions: MoM implant systems with longer necks and smaller cup abduction angles may lead to increased need for revision. Results from this study suggest a need for closer long-term follow-up of MoM THA systems.