HIV-infected Donors Research Articles

HIV+ deceased donor referrals: A national survey of organ procurement organizations.

HIV-infected (HIV+) donor organs can be transplanted into HIV+ recipients under the HIV Organ Policy Equity (HOPE) Act. Quantifying HIV+ donor referrals received by organ procurement organizations (OPOs) is critical for HOPE Act implementation. We surveyed the 58 USA OPOs regarding HIV+ referral records and newly discovered HIV+ donors. Using data from OPOs that provided exact records and CDC HIV prevalence data, we projected a national estimate of HIV+ referrals. Fifty-five (95%) OPOs reported HIV+ referrals ranging from 0 to 276 and newly discovered HIV+ cases ranging from 0 to 10 annually. Six OPOs in areas of high HIV prevalence reported more than 100 HIV+ donor referrals. Twenty-seven (47%) OPOs provided exact HIV+ referral records and 28 (51%) OPOs provided exact records of discovered HIV+ cases, totaling 1450 HIV+ referrals and 39 discovered HIV+ donors in the prior year. These OPOs represented 67% and 59% of prevalent HIV cases in the USA; thus, we estimated 2164 HIV+ referrals and 66 discovered HIV+ cases nationally per year. OPOs reported a high volume of HIV+ referrals annually, of which a subset will be medically eligible for donation. Particularly in areas of high HIV prevalence, OPOs require ongoing support to implement the HOPE Act.

Which Infectious Blood Donors Could Be Identified by the Donor History Questionnaire - Comparison of Blood Donors Infected with HIV or HCV with Notified Cases from General Population in Germany

Background: Potential risks for transfusion-transmissible infections are identified by donor history questionnaires (DHQs), and donors with higher risks are deferred from donation. We assessed to which extent the currently used DHQs support the identification of infections among blood donors. Methods: Between 2006 and 2013, we analyzed data from notified HIV and HCV cases in the general population and positive blood donors in Germany. Logistic regressions were used to identify relevant infection risks. We estimated the possible effect of improved capture of risk factors for donor selection by calculation of population attributable fractions (PAF). Results: Risky sexual contacts - MSM as well as heterosexual contacts - were the most prominent infection risks among HIV-infected donors. Whereas MSM contacts were significantly less reported by donors than by cases from the general population, 58% of donors disclosed heterosexual risks compared to 26% of notified cases. The complete identification of heterosexual risk contacts might prevent acceptance of 53% of HIV-infected donors. HCV-infected donors were more likely to report heterosexual exposure, imprisonment, and piercing/tattoo than notified HCV cases. Improved recording of piercing/tattoo could prevent acceptance of 16% of HCV-infected donors. Conclusion: Donor selection should be improved with special attention to the identification of (hetero)sexual risk factors, invasive procedures (piercing/tattoo and imprisonment) applying well-designed DHQs, effective donor education, and confidential environment in all steps of the selection process.

Lower endometrial receptivity in HIV-infected women receiving oocyte donation: a comorbidity of HIV infection?

STUDY QUESTIONAre the reproductive outcomes of HIV-infected donor oocyte recipient women comparable to those of non-infected women?SUMMARY ANSWERHIV-infected women have lower clinical pregnancy and live birth rates than non-infected women.WHAT IS ALREADY KNOWNThe literature on the effect of HIV infection on reproductive outcome is scarce at best; the only report to date comparing oocyte donation cycles in HIV-infected women versus non-infected controls found no differences in pregnancy rates between the two groups. However, this study was performed nearly a decade ago and did not evaluate the effect of immuno-virological characteristics of oocyte recipients or the HIV antiretroviral therapy effect.STUDY DESIGN SIZE, AND DURATIONThis is a matched-cohort study including 514 oocyte donation cycles, 257 from HIV-infected women and 257 non-infected controls, performed between April 2004 and November 2014.PARTICIPANTS/MATERIALS, SETTING, AND METHODEach cycle of an HIV-infected woman (n = 257) was matched with a cycle of a non-infected woman (1:1). Biochemical pregnancy, clinical pregnancy, ongoing pregnancy and live birth in the two groups were compared using a multivariate logistic regression analysis. The effect of antiretroviral treatment options on pregnancy outcomes of HIV-infected women was analyzed using a logistic regression model adjusted for time elapsed from diagnosis, and CD4 levels and viral load prior to embryo transfer.MAIN RESULTS AND THE ROLE OF CHANCECycles of HIV-infected patients receiving oocyte donation presented lower pregnancy and live birth rates than matched non-infected controls. Treatment options and infection parameters analyzed do not seem to affect the reproductive results in HIV-infected women. The variable most influencing pregnancy outcomes was the number of transferred embryos; lower pregnancy rates were obtained after single embryo transfer.LIMITATIONS REASONS FOR CAUTIONPatients with HIV infection have specific health issues, such as infection/treatment side effects, which makes it impossible to find a matching control group of non-infected patients for these variables.WIDER IMPLICATIONS OF THE FINDINGSHIV-infected women receiving donated oocytes present lower pregnancy rates when compared to non-infected controls, regardless of the antiretroviral treatment followed. The complexity of the treatments (both in medication types and combinations) makes it difficult to define whether any one treatment option is better than the others in terms of pregnancy outcomes in oocyte recipients.STUDY FUNDING/COMPETING INTERESTSNone.TRIAL REGISTRATION NUMBERNot applicable.

First UK case report of kidney transplantation from an HIV-infected deceased donor to two HIV-infected recipients.

Kidney transplantation is now considered the treatment of choice for many human immunodeficiency virus (HIV)-infected patients with end-stage renal disease (ESRD). Graft survival rates using HIV-negative donors and carefully selected HIV-positive ESRD patients are similar to those observed in HIV-uninfected kidney transplant recipients. To address the relative shortfall in donated organs it has been proposed that organs from HIV-infected deceased donors might be allocated to HIV-infected patients on the transplant waiting list. Preliminary experience in South Africa reports promising short-term outcomes in a small number of HIV-infected recipients of kidney transplants from HIV-infected donors. We sought to replicate this experience in the UK by accepting kidney offers from HIV infected deceased donors for patients with HIV-infection on the kidney transplant waiting list. Here we report the UK’s first cases of kidney transplantation between HIV-positive donors and recipients.

The Times, They are a-Changing: HOPE for HIV-to-HIV Organ Transplantation.

HIV-infected persons who achieve undetectable viral loads on antiretroviral therapy currently have near-normal lifespans. Liver disease is a major cause of non-AIDS-related deaths, and as a result of longer survival, the prevalence of end-stage renal disease in HIV is increasing. HIV-infected persons undergoing organ transplantation generally achieve comparable patient and graft survival rates compared to their HIV-uninfected counterparts, despite a nearly threefold increased risk of acute rejection. However, the ongoing shortage of suitable organs can limit transplantation as an option, and patients with HIV have higher waitlist mortality than others. One way to solve this problem would be to expand the donor pool to include HIV-infected individuals. The results of a South Africa study involving 27 HIV-to-HIV kidney transplants showed promise, with 3- and 5-year patient and graft survival rates similar to those of their HIV-uninfected counterparts. Similarly, individual cases of HIV-to-HIV liver transplantation from the United Kingdom and Switzerland have also shown good results. In the United States, HIV-to-HIV kidney and liver transplants are currently permitted only under a research protocol. Nevertheless, areas of ambiguity exist, including streamlining organ allocation practices, optimizing HIV-infected donor and recipient selection, managing donor-derived transmission of a resistant HIV strain, determining optimal immunosuppressive and antiretroviral regimens, and elucidating the incidence of rejection in HIV-to-HIV solid organ transplant recipients.

Cytomegalovirus infection in HIV-infected and uninfected individuals is characterized by circulating regulatory T cells of unconstrained antigenic specificity.

Cytomegalovirus (CMV) infection is associated with immune-suppression in immune-compromised hosts and old adults. We previously showed that ex vivo CMV restimulation of peripheral blood mononuclear cells (PBMC) of CMV-seropositive volunteers expanded CD4+CD27-CD28- regulatory T cells (Tregs). Here we evaluate the phenotype and function of circulating CD4+CD27-CD28- T cells of CMV-seropositive adults. Compared with CMV-seronegative, CMV-seropositive adults had 10-fold higher CD4+CD27-CD28-% T cells in PBMC. Circulating CD4+CD27-CD28- T cells from both CMV-seropositive and seronegative donors expressed higher levels of TGFβ, granzyme B, CD39, CD147 and IL-35, and lower levels of CD127, compared with their parent circulating CD4+ T cells. However, only CMV-seropositive circulating CD4+CD27-CD28- had increased FOXP3 expression. CD4+CD27-CD28- sorted from the PBMC of CMV-seropositive donors expanded ex vivo in the presence of rhIL2 and inhibited ex vivo proliferation of autologous PBMC restimulated with CMV, varicella-zoster virus or C. albicans antigens. CD4+CD27-CD28- sorted from CMV-seronegative PBMC did not expand in the presence of rhIL2 and did not inhibit autologous PBMC proliferation. CD3+CD27-CD28- circulating T cells (≥80% CD8+) from CMV-seropositive HIV-infected donors also inhibited ex vivo proliferation of autologous PBMC restimulated with CMV or HIV. These data indicate that CMV-seropositive individuals have circulating Tregs that inhibit cell-mediated immune responses to CMV and other antigens and may be contribute to an immune-suppressive effect of CMV infection. Moreover, the phenotypic similarity between circulating CD4+CD27-CD28- Tregs with differentiated effector T cells suggests that the two T-cell subsets might evolve in parallel or in sequence from the same progenitor cells in response to CMV stimulation during reactivations.

Hepatitis E virus antibodies in HIV-infected patients and blood donors from western Poland: A preliminary report.

Hepatitis E virus (HEV) infection is an emerging problem in industrialized countries, including Europe. Little data exists on HEV seroprevalence in Poland. The aim of this study was to assess the prevalence of anti-HEV IgG antibodies in Polish patients infected with the human immunodeficiency virus (HIV) and blood donors. Two hundred and ten individuals (n = 105 of HIV-infected patients and n = 105 of ageand sex-matched blood donors from the same area; 178 men and 32 women), aged 18-50 (median age: 38 years), were tested for the presence of anti-HEV IgG antibodies with the EUROIMMUN Anti-Hepatitis E Virus (HEV) ELISA (IgG) tests (Lübeck, Germany). Additionally, some simple clinical and laboratory data was collected. The overall anti-HEV IgG prevalence was 2.4% (5/210). One HIV-positive patient (0.95%) and 4 blood donors (3.8%) were seropositive (p = 0.1745). All the HEV-exposed individuals were men with a history of travel abroad and no icteric disease in the past. Exposure to HEV infection among Polish HIV patients and blood donors seems to be uncommon. Data on this issue is scarce and conflicting for HIV-infected individuals. Further investigations applying different serological tests and concomitant HEV RNA testing are needed to reliably assess the risk and practical impact of HEV infection in Poland.

Single-cell analysis of HIV-1 transcriptional activity reveals expression of proviruses in expanded clones during ART

Little is known about the fraction of human immunodeficiency virus type 1 (HIV-1) proviruses that express unspliced viral RNA in vivo or about the levels of HIV RNA expression within single infected cells. We developed a sensitive cell-associated HIV RNA and DNA single-genome sequencing (CARD-SGS) method to investigate fractional proviral expression of HIV RNA (1.3-kb fragment of p6, protease, and reverse transcriptase) and the levels of HIV RNA in single HIV-infected cells from blood samples obtained from individuals with viremia or individuals on long-term suppressive antiretroviral therapy (ART). Spiking experiments show that the CARD-SGS method can detect a single cell expressing HIV RNA. Applying CARD-SGS to blood mononuclear cells in six samples from four HIV-infected donors (one with viremia and not on ART and three with viremia suppressed on ART) revealed that an average of 7% of proviruses (range: 2-18%) expressed HIV RNA. Levels of expression varied from one to 62 HIV RNA molecules per cell (median of 1). CARD-SGS also revealed the frequent expression of identical HIV RNA sequences across multiple single cells and across multiple time points in donors on suppressive ART consistent with constitutive expression of HIV RNA in infected cell clones. Defective proviruses were found to express HIV RNA at levels similar to those proviruses that had no obvious defects. CARD-SGS is a useful tool to characterize fractional proviral expression in single infected cells that persist despite ART and to assess the impact of experimental interventions on proviral populations and their expression.

Tim-3 is a Marker of Plasmacytoid Dendritic Cell Dysfunction during HIV Infection and Is Associated with the Recruitment of IRF7 and p85 into Lysosomes and with the Submembrane Displacement of TLR9.

In chronic diseases, such as HIV infection, plasmacytoid dendritic cells (pDCs) are rendered dysfunctional, as measured by their decreased capacity to produce IFN-α. In this study, we identified elevated levels of T cell Ig and mucin-domain containing molecule-3 (Tim-3)-expressing pDCs in the blood of HIV-infected donors. The frequency of Tim-3-expressing pDCs correlated inversely with CD4 T cell counts and positively with HIV viral loads. A lower frequency of pDCs expressing Tim-3 produced IFN-α or TNF-α in response to the TLR7 agonists imiquimod and Sendai virus and to the TLR9 agonist CpG. Thus, Tim-3 may serve as a biomarker of pDC dysfunction in HIV infection. The source and function of Tim-3 was investigated on enriched pDC populations from donors not infected with HIV. Tim-3 induction was achieved in response to viral and artificial stimuli, as well as exogenous IFN-α, and was PI3K dependent. Potent pDC-activating stimuli, such as CpG, imiquimod, and Sendai virus, induced the most Tim-3 expression and subsequent dysfunction. Small interfering RNA knockdown of Tim-3 increased IFN-α secretion in response to activation. Intracellular Tim-3, as measured by confocal microscopy, was dispersed throughout the cytoplasm prior to activation. Postactivation, Tim-3 accumulated at the plasma membrane and associated with disrupted TLR9 at the submembrane. Tim-3-expressing pDCs had reduced IRF7 levels. Furthermore, intracellular Tim-3 colocalized with p85 and IRF7 within LAMP1+ lysosomes, suggestive of a role in degradation. We conclude that Tim-3 is a biomarker of dysfunctional pDCs and may negatively regulate IFN-α, possibly through interference with TLR signaling and recruitment of IRF7 and p85 into lysosomes, enhancing their degradation.

Phylogenetic evidence for underreporting of male‐to‐male sex among human immunodeficiency virus–infected donors in the Netherlands and Flanders

Separate transmission networks for human immunodeficiency virus (HIV) coexist. Molecular typing of viral genomes can provide insight in HIV transmission routes in donors for whom risk behavior-based donor selection failed. This study includes all HIV-infected Dutch and Flemish donors in the period 2005 to 2014 (n = 55). Part of the HIV polymerase (pol) gene was amplified, sequenced, and compared with more than 10,000 HIV strains obtained from HIV-infected Dutch and Flemish patients. The most likely transmission route was determined based on HIV phylogeny and the donor's self-reported risk behavior during the exit interview. HIV-infected donors were predominantly male (69%), were repeat donors (73%), were born in the Netherlands or Belgium (95%), and harbored HIV Subtype B (68%). Seventy-five percent of HIV-infected male donors were part of robust phylogenetic clusters linked to male-to-male sex, while only 24% of HIV-infected male donors reported male-to-male sex during posttest counseling. Sex between men and women accounted for 13% of HIV infections in male donors and 93% of HIV infections in female donors based on phylogenetic analysis. Only 40% of HIV-infected female donors had HIV Subtype B; 65% of female donors reported a foreign partner and indeed HIV sequences interspersed with sequences from HIV-endemic areas abroad, in particular sub-Saharan Africa. HIV typing helps to understand HIV transmission routes in donor populations. We found substantial underreporting of male-to-male sex among HIV-infected male donors. Donor education on HIV risk factors and the danger of window-period donations and a donor environment that encourages frank disclosure of sexual behavior will contribute to a decrease of HIV-infected donors.

An Exception to the Rule or a Rule for the Exception? The Potential of Using HIV-Positive Donors in Canada.

Selected human immunodeficiency virus (HIV)-infected patients with end organ failure can safely receive an organ transplant from an HIV uninfected donor. Recent demonstration of the short term safety of organ transplantation between HIV-infected persons prompted a change in US American law to allow such transplantations. Prompted by the recent completion of the first organ transplantation between HIV-infected persons in Canada, we review Canadian law regarding the use of organs from HIV-infected donors, estimate the number of potential HIV-infected donors in Canada, and critically review considerations related to advancing organ transplantation from HIV-infected donors in Canada. Existing legislation allows organ transplantation from an HIV-infected donor under exceptional medical circumstances and therefore no change in legislation is required to increase utilization of organs from HIV-infected donors for transplantation in Canada. Among 335,793 hospital deaths between 2005 and 2009 in Canadian provinces excluding Quebec, 39 potential HIV-infected donors were identified. The actual number of HIV potential donors is estimated to be approximately 60% lower (3-5 potential donor per year), if the absence of viremia is required for transplantation. Although offering all Canadians the opportunity to donate organs is a laudable goal, further research to understand the need for HIV-positive donors and the willingness of HIV-positive recipients to accept organs from HIV-positive donors is needed to inform future policy regarding organ donation from HIV-infected persons in Canada.

Blood safety implications of donors using HIV pre-exposure prophylaxis.

HIV pre-exposure prophylaxis (PrEP) is the use of one or more antiretroviral medications (in combination) to prevent HIV infection. The most commonly used PrEP medication (Truvada® , Gilead Sciences, Inc.) acts by inhibiting HIV-1 reverse transcriptase. If someone who is using PrEP unknowingly becomes HIV infected (termed 'PrEP breakthrough infection'), there may be suppressed viral replication resulting in a virus level undetectable by the most sensitive HIV NAT. Failure to seroconvert and seroreversion (loss of previously detectable HIV antibodies) have also both been observed with 2nd, 3rd and 4th generation screening immunoassays, as well as Western blot assays. If such a person was tested in the course of donating blood, the results may therefore be difficult to interpret. The index of suspicion for possible PrEP 'interference' should be highest in the context of concomitant low-level positive or 'greyzone' reactivity on HIV NAT and serological tests, which is an unusual pattern in acutely HIV-infected blood donors. Another possibility is detectable HIV RNA with negative HIV serology (i.e. a potential 'NAT yield' case) but without subsequent HIV seroconversion (or disappearance of HIV RNA). Excluding antiretroviral therapy or PrEP use by the donor in such circumstances would be important. The current rarity of PrEP breakthrough infection indicates that any potential safety risk is likely very small. However, considering the increasing use of PrEP we feel it is prudent for those interpreting HIV donor screening test results to consider the potential for PrEP interference.

Mapping Polyclonal HIV-1 Antibody Responses via Next-Generation Neutralization Fingerprinting.

Computational neutralization fingerprinting, NFP, is an efficient and accurate method for predicting the epitope specificities of polyclonal antibody responses to HIV-1 infection. Here, we present next-generation NFP algorithms that substantially improve prediction accuracy for individual donors and enable serologic analysis for entire cohorts. Specifically, we developed algorithms for: (a) selection of optimized virus neutralization panels for NFP analysis, (b) estimation of NFP prediction confidence for each serum sample, and (c) identification of sera with potentially novel epitope specificities. At the individual donor level, the next-generation NFP algorithms particularly improved the ability to detect multiple epitope specificities in a sample, as confirmed both for computationally simulated polyclonal sera and for samples from HIV-infected donors. Specifically, the next-generation NFP algorithms detected multiple specificities in twice as many samples of simulated sera. Further, unlike the first-generation NFP, the new algorithms were able to detect both of the previously confirmed antibody specificities, VRC01-like and PG9-like, in donor CHAVI 0219. At the cohort level, analysis of ~150 broadly neutralizing HIV-infected donor samples suggested a potential connection between clade of infection and types of elicited epitope specificities. Most notably, while 10E8-like antibodies were observed in infections from different clades, an enrichment of such antibodies was predicted for clade B samples. Ultimately, such large-scale analyses of antibody responses to HIV-1 infection can help guide the design of epitope-specific vaccines that are tailored to take into account the prevalence of infecting clades within a specific geographic region. Overall, the next-generation NFP technology will be an important tool for the analysis of broadly neutralizing polyclonal antibody responses against HIV-1.

Trace Element Levels, Cytokine Profile and Immune Activation Status in Plasma among Repeat Blood Donors with Asymptomatic HIV-1, HBV and HCV Infection

Imbalance of essential trace elements viz. Zinc, Selenium, Iron, Copper and Magnesium has been reported to influence disease course in HIV-1, HBV and HCV infections by altering immune status. A study was taken up to examine plasma levels of Th1 (IFN-γ and IL-2) and Th2 (IL-4 and IL-10) categories of cytokines and immune activation markers (TNF-α, TNFR I and TNFR II) in an asymptomatic group of HIV-1, HBV and HCV infected blood donors in relation to trace elements. Plasma levels of Zn, Se and Mg were depressed in all the three groups of blood donors (P γ were depressed in all the three groups of blood donors (P γ, and in HBV infection while positive correlations were found between Mg and TNFR I and TNFR II and Se with TNFR II. HCV infection showed a positive correlation between Se and IFN-γ (P < 0.001), Mg and IL-4 (P = 0.02), Fe and IL-10 (P < 0.01). The present study reveals possible relationship between trace element level alterations and alterations in cytokine and immune activation levels in HIV-1, HBV and HCV infection.

Diversity of Antiviral IgG Effector Activities Observed in HIV-Infected and Vaccinated Subjects.

Diverse Ab effector functions mediated by the Fc domain have been commonly associated with reduced risk of infection in a growing number of nonhuman primate and human clinical studies. This study evaluated the anti-HIV Ab effector activities in polyclonal serum samples from HIV-infected donors, VAX004 vaccine recipients, and healthy HIV-negative subjects using a variety of primary and cell line-based assays, including Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cell-mediated viral inhibition, and Ab-dependent cellular phagocytosis. Additional assay characterization was performed with a panel of Fc-engineered variants of mAb b12. The goal of this study was to characterize different effector functions in the study samples and identify assays that might most comprehensively and dependably capture Fc-mediated Ab functions mediated by different effector cell types and against different viral targets. Deployment of such assays may facilitate assessment of functionally unique humoral responses and contribute to identification of correlates of protection with potential mechanistic significance in future HIV vaccine studies. Multivariate and correlative comparisons identified a set of Ab-dependent cell-mediated viral inhibition and phagocytosis assays that captured different Ab activities and were distinct from a group of ADCC assays that showed a more similar response profile across polyclonal serum samples. The activities of a panel of b12 monoclonal Fc variants further identified distinctions among the ADCC assays. These results reveal the natural diversity of Fc-mediated Ab effector responses among vaccine recipients in the VAX004 trial and in HIV-infected subjects, and they point to the potential importance of polyfunctional Ab responses.

Ultrasensitive single-genome sequencing: accurate, targeted, next generation sequencing of HIV-1 RNA.

BackgroundAlthough next generation sequencing (NGS) offers the potential for studying virus populations in unprecedented depth, PCR error, amplification bias and recombination during library construction have limited its use to population sequencing and measurements of unlinked allele frequencies. Here we report a method, termed ultrasensitive Single-Genome Sequencing (uSGS), for NGS library construction and analysis that eliminates PCR errors and recombinants, and generates single-genome sequences of the same quality as the “gold-standard” of HIV-1 single-genome sequencing assay but with more than 100-fold greater depth.ResultsPrimer ID tagged cDNA was synthesized from mixtures of cloned BH10 wild-type and mutant HIV-1 transcripts containing ten drug resistance mutations. First, the resultant cDNA was divided and NGS libraries were generated in parallel using two methods: uSGS and a method applying long PCR primers to attach the NGS adaptors (LP-PCR-1). Second, cDNA was divided and NGS libraries were generated in parallel comparing 3 methods: uSGS and 2 methods adapted from more recent reports using variations of the long PCR primers to attach the adaptors (LP-PCR-2 and LP-PCR-3). Consistently, the uSGS method amplified a greater proportion of cDNAs, averaging 30% compared to 13% for LP-PCR-1, 21% for LP-PCR-2 and 14% for LP-PCR-3. Most importantly, when the uSGS sequences were binned according to their primer IDs, 94% of the bins did not contain PCR recombinant sequences versus only 55, 75 and 65% for LP-PCR-1, 2 and 3, respectively. Finally, when uSGS was applied to plasma samples from HIV-1 infected donors, both frequent and rare variants were detected in each sample and neighbor-joining trees revealed clusters of genomes driven by the linkage of these mutations, showing the lack of PCR recombinants in the datasets.ConclusionsThe uSGS assay can be used for accurate detection of rare variants and for identifying linkage of rare alleles associated with HIV-1 drug resistance. In addition, the method allows accurate in-depth analyses of the complex genetic relationships of viral populations in vivo.

HIV-Positive to HIV-Positive Liver Transplantation: One Successful Outcome

Experience with liver and kidney transplantation into HIV-infected recipients has been promising, with outcomes approaching those in HIV-negative recipients. In 2015, President Obama signed the HOPE (HIV Organ Policy Equity) Act, which allows transplantation in the U.S. using organs from HIV-infected donors into HIV-infected recipients. However, little experience with HIV–positive-to-positive liver transplantation has been reported in the scientific literature. This case report from the U.K. details the course of a patient with HIV and hepatitis C virus (HCV) …

Approaches to the induction of HIV broadly neutralizing antibodies.

A vaccine that elicits antibody responses that can neutralize the diversity of HIV clades has not yet been achieved, and is a major focus of HIV vaccine research. Here, we provide an update on the barriers to eliciting such antibodies, and how advances in immunogen design may circumvent these roadblocks, focusing on data published in the last year. Studies of how broadly neutralizing antibodies (bNAbs) develop in HIV-infected donors continue to produce key insights, suggesting that for some viral targets there are common pathways to developing breadth. Germline-targeting strategies, that aim to recruit rare precursors of bNAbs, have shown promise in immunogenicity studies, and structural biology has led to advances in immunogen design. Mapping of strain-specific tier 2 vaccine responses has highlighted the challenges that remain in driving antibodies toward breadth. Elucidation of the HIV envelope structure, together with an understanding of how bNAbs emerge in vivo has guided the design of new immunogens and vaccine strategies that show promise for eliciting protective antibodies.

Extensive Genetic Diversity of HIV-1 in Incident and Prevalent Infections among Malaysian Blood Donors: Multiple Introductions of HIV-1 Genotypes from Highly Prevalent Countries.

Transfusion-transmissible infections including HIV-1 continue to pose major risks for unsafe blood transfusions due to both window phase infections and divergent viruses that may not be detected by donor screening assays. Given the recent emergence of several HIV-1 circulating recombinant forms (CRFs) in high-risk populations in the Southeast Asia region, we investigated the genetic diversity of HIV-1 among the blood donors in Kuala Lumpur, Malaysia. A total of 211 HIV-positive plasma samples detected among 730,188 donations to the National Blood Centre between 2013 and 2014 were provided (90.5% male, median age: 27.0 years old). Recent or long-term infection status at the time of donation was determined using a limiting antigen avidity enzyme immunoassay (LAg-Avidity EIA). HIV-1 gag-pol genes were amplified and sequenced from residual plasma for 149 cases followed by genotype determination using phylogenetic and recombination analyses. Transmitted antiretroviral resistance mutations were not observed among the blood donors, among which 22.7% were classified as recent or incident infections. Major circulating HIV-1 genotypes determined by neighbour-joining phylogenetic inference included CRF01_AE at 40.9% (61/149), CRF33_01B at 21.5% (32/149), and subtype B at 10.1% (15/149). Newly-described CRFs including CRF54_01B circulated at 4.0%, CRF74_01B at 2.0%, and CRF53_01B and CRF48_01B at 0.7% each. Interestingly, unique HIV-1 genotypes including African subtype G (8.7%), CRF45_cpx (1.3%), CRF02_AG (0.7%) and CRF07_BC (0.7%) from China were detected for the first time in the country. A cluster of subtype G sequences formed a distinct founder sub-lineage within the African strains. In addition, 8.7% (13/149) of HIV-infected donors had unique recombinant forms (URFs) including CRF01_AE/B' (4.7%), B'/C (2.7%) and B'/G (1.3%) recombinants. Detailed analysis identified similar recombinant structures with shared parental strains among the B'/C and B'/G URFs, some of which were sequenced from recently infected individuals, indicating the possible emergence and on-going spread of foreign clades of CRF candidates among the local population. The findings demonstrate extensive molecular complexity of HIV-1 among the infected blood donors in Malaysia, driven in part by the increased spread of recently described CRFs and multiple introductions of previously unreported genotypes from highly prevalent countries.

Identification of novel antagonistic anti-PD-1 antibodies that are non-blocking of the PD-1 / PD-L1 interaction.

3072 Background: Monoclonal antibodies (mAbs) that act through PD-1 blockade have had significant clinical success as cancer immunotherapeutic agents particularly in melanoma and non-small cell lung cancers with considerably lower toxicities compared to similar therapies. Current anti-PD-1 Abs have relied on the blockade of the PD-1/PD-L1 interaction. Methods: A screening strategy was established to identify a panel of mAbs that bind with high affinity to diverse epitopes on PD-1. In vitro functional activity of the mAbs was evaluated by the capacity to restore proliferation to exhausted CD8 T cells from viremic HIV infected donors and using a mixed lymphocyte reaction assay (MLR). Results: Our studies show that antagonistic mAbs targeting PD-1 can be blocking or non-blocking of the PD-1/PD-L1 interaction. Compared to benchmark blocking mAbs (pembrolizumab and nivolumab), an epitope specific set of non-blocking anti-PD-1 mAbs have equivalent antagonistic activity in: 1) restoring proliferation to exhausted HIV specific CD8 T cells and 2) promoting proliferation and up-regulating IFNγ production of CD4 T cells in a MLR assay. Importantly, combinations of blocking and non-blocking anti-PD-1 mAbs synergize in significantly improving functional activity as to that achieved with either therapeutic agent alone. Conclusions: A panel of non-blocking mAbs targeting PD-1 with strong antagonistic activity have been generated and extensively characterized in their ability to recover exhausted antigen-specific CD4 and CD8 T cells and to improve a variety of functions. Importantly, combination of non-blocking with blocking anti-PD-1 mAbs resulted in significantly improved functional activity. These results provide the scientific rationale to investigate whether combination therapy may enhance therapeutic benefit in cancer immunotherapy or whether non-blocking anti-PD-1 Abs may be effective in low PD-L1 positive tumors. Humanized non-blocker anti-PD-1 mAbs have been generated and are being advanced into clinical development.