Allogeneic immunity clears latent virus following allogeneic stem cell transplantation in SIV-infected ART-suppressed macaques.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) from donors lacking C-C chemokine receptor 5 (CCR5Δ32/Δ32) can cure HIV, yet mechanisms remain speculative. To define how alloHSCT mediates HIV cure, we performed MHC-matched alloHSCT in SIV+, anti-retroviral therapy (ART)-suppressed Mauritian cynomolgus macaques (MCMs) and demonstrated that allogeneic immunity was the major driver of reservoir clearance, occurring first in peripheral blood, then peripheral lymph nodes, and finally in mesenteric lymph nodes draining the gastrointestinal tract. While allogeneic immunity could extirpate the latent viral reservoir and did so in two alloHSCT-recipient MCMs that remained aviremic >2.5 years after stopping ART, in other cases, it was insufficient without protection of engrafting cells afforded by CCR5-deficiency, as CCR5-tropic virus spread to donor CD4+ T cells despite full ART suppression. These data demonstrate the individual contributions of allogeneic immunity and CCR5 deficiency to HIV cure and support defining targets of alloimmunity for curative strategies independent of HSCT.

Viral opportunistic infections in Mauritian cynomolgus macaques undergoing allogeneic stem cell transplantation mirror human transplant infectious disease complications.

Allogeneic hematopoietic stem cell transplantation (HSCT) and xenotransplantation are accompanied by viral reactivations and virus-associated complications resulting from immune deficiency. Here, in a Mauritian cynomolgus macaque model of fully MHC-matched allogeneic HSCT, we report reactivations of cynomolgus polyomavirus, lymphocryptovirus, and cytomegalovirus, macaque viruses analogous to HSCT-associated human counterparts BK virus, Epstein-Barr virus, and human cytomegalovirus. Viral replication in recipient macaques resulted in characteristic disease manifestations observed in HSCT patients, such as polyomavirus-associated hemorrhagic cystitis and tubulointerstitial nephritis or lymphocryptovirus-associated post-transplant lymphoproliferative disorder. However, in most cases, the reconstituted immune system, alone or in combination with short-term pharmacological intervention, exerted control over viral replication, suggesting engraftment of functional donor-derived immunity. Indeed, the donor-derived reconstituted immune systems of two long-term engrafted HSCT recipient macaques responded to live attenuated yellow fever 17D vaccine (YFV 17D) indistinguishably from untransplanted controls, mounting 17D-targeted neutralizing antibody responses and clearing YFV 17D within 14 days. Together, these data demonstrate that this macaque model of allogeneic HSCT recapitulates clinical situations of opportunistic viral infections in transplant patients and provides a pre-clinical model to test novel prophylactic and therapeutic modalities.

Clinical applications of pharmacogenomics guided warfarin dosing.

AIM OF THE REVIEW: To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. METHOD: We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. RESULTS: Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. CONCLUSION: Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use.

Clinical applications of pharmacogenomics guided warfarin dosing.

AIM OF THE REVIEW: To assess the state of the literature concerning pharmacogenomic testing in patients requiring vitamin K antagonists, specifically warfarin. METHOD: We conducted a literature search of MEDLINE and International Pharmaceutical Abstracts using the following words: warfarin, pharmacogenetic, and pharmacogenomic. The search results were reviewed by the authors and papers concerning pharmacogenomic testing in warfarin dosing were procured and reviewed. Additionally bibliographies of papers procured were also examined for other studies. The authors focused on clinical trials concerning the use of pharmacogenomic testing in warfarin dosing. RESULTS: Although numerous studies have demonstrated that a significant portion of warfarin dosing variability can be explained by genetic polymorphisms, few prospective studies have been conducted that examine the integration of this information in practical dosing situations. Those that have, have shown that using pharmacogenomic information improves initial dosing estimates and decreases the need for frequent clinic visits and laboratory testing. Data showing a reduction in serious bleeding events is sparse. Cost-effectiveness analyses have generally shown a small but positive effect with pharmacogenomic testing in patients receiving warfarin. CONCLUSION: Several studies have shown that pharmacogenomic testing for warfarin dosing is more accurate that other dosing schemes. Pharmacogenomic testing improves time to a therapeutic international normalized ratio while requiring fewer dosing adjustments. Patients who require higher or lower than usual doses seem to benefit the most. The cost-effectiveness of pharmacogenomic testing as well as preventing of outcomes such as bleeding or thrombosis are not yet elucidated. Pharmacists, especially those in a community setting can play a role in this new technology by educating prescribers and patients concerning pharmacogenomic testing, and by developing and using dosing protocols that incorporate its use.