Objective: Higher incidence of osteopenia and osteoporosis underlie increased rates of fragility fracture in HIV infection. B cells are a major source of osteoprotegerin (OPG), an inhibitor of the key osteoclastogenic cytokine receptor activator of nuclear factor-κB ligand (RANKL). We previously showed that higher B-cell RANKL/OPG ratio contributes to HIV-induced bone loss. T-cell OPG production in humans, however, remains undefined and the contribution of T-cell OPG and RANKL to HIV-induced bone loss has not been explored. Design: We investigated T-cell OPG and RANKL production in ART-naive HIV-infected and uninfected individuals in relation to indices of bone loss in a cross-sectional study.
Methods: T-cell RANKL and OPG production was determined by intracellular staining and flow cytometry, and plasma levels of bone resorption markers were determined by ELISA.
Results: We demonstrate for the first time in-vivo human T-cell OPG production, which was significantly lower in HIV-infected individuals and was coupled with moderately higher T-cell RANKL production, resulting in a significantly higher T-cell RANKL/OPG ratio. T-cell RANKL/OPG ratio correlated significantly with BMD-derived z-scores at the hip, lumbar spine and femur neck in HIV-infected individuals with CD4+ T-cell counts at least 200 cells/μl but not in those with lower counts.
Conclusion: Our data suggest that T cells may be a physiologically relevant source of OPG and T-cell RANKL/OPG imbalance is associated with HIV-induced bone loss in CD4+ T-cell-sufficient patients. Both B and T lymphocytes may thus contribute to HIV-induced bone loss.
by
Robert A. Rasmussen;
Nagadenahalli B. Siddappa;
Samir K. Lakhashe;
Jennifer Watkins;
Francois Villinger;
Chris Ibegbu;
Ruth H. Florese;
Marjorie Robert-Guroff;
David C. Montefiori;
Donald N. Forthal;
David O'Connor;
Ruth M. Ruprecht
OBJECTIVE:: To characterize the correlates of protection from systemic infection in a vaccinated rhesus macaque, RAt-9, which had been challenged sequentially with two related clade C simian/human immunodeficiency viruses (SHIV-Cs) yet remained aviremic for more than 5 years despite indirect evidence of cryptic infection.
DESIGN:: To measure long-term anti-SHIV-C immunity, host genetics and gene-expression patterns for protective correlates. METHODS:: Long-term immune reactivity was evaluated and identification of virus in RAt-9 was attempted by RT-PCR analysis of concentrated plasma and blood transfer to CD8 cell-depleted infant macaques. Full MHC genotyping of RAt-9, TRIM5α and KIR3DL allelic expression analysis of PBMC, and microarray gene expression analysis were performed.
RESULTS:: All attempts to detect/isolate virus, including blood transfer to CD8 cell-depleted infant rhesus macaques, were negative, and the animal maintained normal levels of memory CD4 T cells in both peripheral blood and gut tissues. However, RAt-9 maintained high levels of anti-SHIV-C humoral and cellular immunity, including reactivity to nonvaccine neoantigens (Nef and Rev), up to 63 months postinitial challenge, suggesting chronic sub-threshold infection. RAt-9 expressed the Mamu A*001 allele negative for B*008 and B*017, had a B13 serotype, and had increased expression of killer-cell immunoglobulin-like receptors (KIRs) previously linked to favorable outcomes of lentiviral infection. Elements of the gene expression profiling coincided with genotyping results. RAt-9 also displayed CD8 cell noncytotoxic antiviral response (CNAR) activity. CONCLUSION:: Monkey RAt-9 is the first example of a virus-exposed, persistently aviremic animal that has maintained long-term, high-level cellular and humoral antiviral immunity in the absence of an identifiable cryptic reservoir.
by
Ellen S. Chan;
Alan L. Landay;
Todd T. Brown;
Heather J. Ribaudo;
Paria Mirmonsef;
Ighoverha Ofotokun;
M. Neale Weitzmann;
Jeffrey Martinson;
Karin L. Klingman;
Joseph J. Eron;
Carl J. Fichtenbaum;
Jill Plants;
Babafemi O. Taiwo
Objective: Studies exploring the immunologic effects of maraviroc (MVC) have produced mixed results; hence, it remains unclear whether MVC has unique immunologic effects in comparison with other antiretroviral drugs. We sought to determine whether MVC has differential effects compared with tenofovir disoproxil fumarate (TDF) during initial antiretroviral therapy. Design: Prospective study in AIDS Clinical Trials Group A5303, a double-blind, placebo-controlled trial (N=262) of MVC vs. TDF, each combined with boosted darunavir and emtricitabine. Methods: A total of 31 cellular and soluble biomarkers were assayed at weeks 0 and 48. Polychromatic flow cytometry was performed on cryopreserved peripheral blood mononuclear cells. Soluble markers were assayed in plasma using ELISA kits. Analyses were as treated. Results: Analyses included 230 participants (119 in MVC arm and 111 in TDF arm). Over 48 weeks of treatment, no significant differences were detected in declines in markers of inflammation and activation with MVC vs. TDF. A greater CD4 + T-cell count increase (median + 234 vs. + 188 cells/μl, P=0.036), a smaller CD8 + T-cell count decrease (-6 vs. -109 cells/μl, P=0.008), and a smaller CD4 + :CD8 + ratio increase (0.26 vs. 0.39, P=0.003) occurred with MVC. Among participants with a baseline CD4 + :CD8 + ratio less than 1, a smaller proportion of MVC group normalized to a ratio greater than 1 at week 48 (15 and 36%, P < 0.001). Conclusion: MVC resulted in less improvement in the CD4 + :CD8 + ratio driven by greater increase in CD4 + cell count but smaller decline in CD8 + cell count. Changes in soluble or cellular biomarkers of inflammation and immune activation were not different between MVC and TDF.