bluuebunny/crossref_metadata_2025 huggingface dataset:
P-D6 Elevated plasma HIV RNA level is associated with impaired neurocognitive function among HIV-1 infected patients in Nigeria
Authors: Jumare Jibreel , El-Kamary Samer , Magder Laurence , Hungerford Laura , Umlauf Anya , Cherner Mariana , Abimiku Alash'le , Charurat Man
Published: April 2018

Introduction:

Plasma HIV RNA level has been shown to correlate with HIV disease progression, morbidity and mortality. We examined the association between levels of plasma HIV RNA and cognitive function among patients in Nigeria.

Methods:

A total of 179 HIV-1 infected participants with available plasma HIV RNA results and followed longitudinally for up to 2 years were included in this study. Blood samples from participants were used for the measurement of plasma HIV RNA and CD4+ T cell count. Utilizing demographic and practice effect adjusted T scores obtained from a 7-domain neuropsychological test battery, cognitive status was determined by the global deficit score (GDS) approach, with a GDS a 0.5 indicating cognitive impairment.

Results:

In a longitudinal multivariable linear regression analysis, adjusting for CD4 cell count, Beck's depression score, age, gender, years of education, and antiretroviral treatment status, global T scores decreased by 0.35 per log10 increase in Plasma HIV RNA (p = 0328). Adjusting for the same variables in a multivariable logistic regression, the odds of neurocognitive impairment were 30% higher per log10 increase in plasma HIV RNA (OR: 1.28 [95% CI: 1.08 to 1.51]; p = 0.0048). There were statistically significant associations for the speed of information processing, executive and verbal fluency domains in both linear and logistic regression analyses.

Conclusion:

We found a significant association between plasma HIV RNA levels and cognitive function in both baseline (cross-sectional) and longitudinal analyses. However, the latter was significantly attenuated, and appeared to be driven largely by strong associations among antiretroviral naive individuals.
P-D8 New insights on the human anti-HIV-1 Env antibody-mediated cell cytotoxicity (ADCC) against HIV-1 virus: Allosteric regulation of FcRs binding upon antigen engagement
Authors: Orlandi Chiara , Deredge Daniel , Ray Krishanu , Gohain Neelakshi , Tolbert William , Pazgier Marzena , DeVico Anthony , Wintrode Patrick
Published: April 2018

HIV-1 vaccine field is rapidly evolving and a deeper knowledge of the mechanisms of defense against HIV-1 infection is needed. In this regard, several studies highlighted the relevance of the antibody-mediated cell cytotoxicity (ADCC) in the context of HIV-1 infection, linking Fc-effector functions to protection against HIV-1 acquisition. The current model for ADCC activation is based on the concept that antibodies, bound to their respective antigens on the surface of HIV-1 sensitized cells, form aggregates which engage the FcRs, activating the effector cells. Our aim is to understand the molecular basis of ADCC and to identify the critical factors that lead to the triggering of the cytotoxicity against HIV-1 virus. Utilizing multiple approaches, such as ELISA, FCS (Fluorescence Correlation Spectroscopy), H/DX MS (Hydrogen/Deuterium Exchange Mass Spectroscopy) and crystallography, we studied the very first step of ADCC activation: the monovalent binding of viral antigen. Here, we demonstrate an allosteric regulation in anti-HIV gp120 Cluster A mAbs resulting from immune complex (IC) formation with a monomeric gp120-CD4 chimera antigen. We established that IC formation dramatically increases the efficiency of Ab interaction to low affinity FcRs compared to free IgG, impacting, in turn, the activation of the cytotoxicity against HIV-1 positive targets. In conclusion, we believe that monomeric antigen-antibody IC formation might be the very first step of HIV-1-specific ADCC triggering that likely precedes the IgG aggregation required for Fc receptors binding and in turn, effector cell activation. This might be a mechanism that enables the fine tuning of Fc-effector functions in vaccine regimens or HIV-1 passive treatments.
P-E2 The Impact of structured mentor mother support on retention during the first 12 months postpartum among HIV positive women in rural Nigeria
Authors: Fan-Osuala Chinenye , Ramadhani Habib , Erekaha Salome , Anaba Udochisom , Nwanne Gift , Bathnna Miriam , Charurat Manhattan , Sam-Agudu Nadia
Published: April 2018

Introduction:

With the advent of lifelong therapy, interventions that sustain long-term engagement with PMTCT services are needed. We evaluated the impact of a structured peer support program on postpartum PMTCT retention among rural Nigerian women.

Methods:

This prospective cohort study enrolled HIV+ pregnant women from 20 primary healthcare centers (PHCs). Ten PHCs with structured mentor mother (MM) support (training, supervision, client tracking, standard documentation and performance evaluation) were pair-matched with 10 routine unstructured peer support (PS) PHCs. Participants received viral load at 6 months and were followed up to 12 months postpartum. Viral suppression was defined as <20 copies/mL. Retention assessment was based on monthly and bi-monthly clinic visits in the first and second 6 month postpartum periods respectively. Participants with ≥5 of 9 expected visits were considered retained. A logistic regression model with generalized estimating equation was used to evaluate the effect of PS and other factors on retention.

Results:

Of 497 women enrolled, 260 and 237 were exposed to MM and routine PS respectively. Women with MM support (aOR = 6.6, 95% CI 3.4 to 13.1) and viral suppression at 6 months (aOR = 3.1, 95% CI 1.8 to 5.6) had higher odds of retention during the 12 month postpartum period. Age, distance from PHC, religion, gravidity, disclosure & time of diagnosis had no effect on retention.

Discussion:

Structure in peer support programs improved retention. Also, viral suppression had an independent effect on retention, indicating a strong link between adherence and sustained engagement; both being essential for PMTCT.

Conclusion:

Built-in structure can significantly enhance the impact of PS interventions on PMTCT outcomes.
B-104 Cancer vaccine: Tumor immunology meets...Immunology
Authors: Accolla Roberto
Published: April 2018

Although recent therapeutic approaches have revitalized the enthusiasm of the immunological way to combat cancer, still the comprehension of the immunity against tumors is largely incomplete. Due to their specific function, CD8+ T cells with cytolytic activity (CTL) have attracted the attention of most investigators because CTL are considered the main effectors against tumor cells. Nevertheless, CTL activity and persistence are largely dependent on the action of CD4+ T helper cells (TH). Thus establishment of tumorspecific TH cell response is key to the optimal response against cancer. I will describe emerging new strategies to increase the TH cell recognition of tumor antigens. In particular, I will present recent data indicating that tumor cells themselves can act as surrogate antigen presenting cells for triggering TH response if genetically modified to express the MHC class II transcriptional activator CIITA. Indeed, injection of CIITA-modified tumor cells of distinct histological origin and of distinct MHC genetic background into syngeneic recipients induces strong protective and long-lasting adaptive immune response that can be transferred to naive recipients by CD4+ TH cells. Depletion of dendritic cells does not modify the capacity to reject the tumor and to acquire immunological memory. These results challenge the immunological dogma that dendritic cells are the exclusive cells capable of inducing T cell priming. The strategy of modifying tumor cells with CIITA has been applied for the production of a novel generation of anti-tumor vaccine against human hepatocarcinoma that is now in clinical trial.
C-101 Production and properties of SOSIP trimers
Authors: Moore John
Published: April 2018

I will review the progress of our team's projects to produce GMP-quality SOSIP trimers in amounts and quantities appropriate for human clinical trials. The BG505 SOSIP.664 GMP-project has now been completed successfully, yielding ~5 g of trimers. A follow-up on effort to make the germline–bNAb targeting BG505 SOSIP. v4.1-GT1.1 trimer is well underway, using the same core methodologies. The latter trimer was designed at the Amsterdam Medical Center and is very similar to one recently described by Medina-Ramirez et al in J Exp Med.

This project stems from our NIH-funded HIVRAD grant program and the translation phase has been supported and managed by the BMGF and IAVI, reflecting the three funding agencies working together towards a common goal.
C-102 Long-term delivery of antiviral monoclonal antibodies
Authors: Desrosiers Ronald
Published: April 2018

The current availability of an incredible array of monoclonal antibodies (mAbs) with potent neutralizing activity against a broad range of HIV-1 isolates creates attractive possibilities for treatment and prevention. An ability to achieve stable levels of protective mAb concentrations long-term via vector delivery has a number of distinct advantages over repeated passive administrations. These include cost, issues relating to adherence, and convenience. Using AAV as vector, we have achieved stable concentrations of authentic IgG mAb in monkeys in excess of 100 ug per ml of serum for as long as 3.5 years, the longest we have measured. In the one SHIV-infected monkey to which we have successfully delivered two anti-HIV mAbs, viral loads have been impressively suppressed from 11,000 at the time of AAV administration to below the limit of detection for more than 22 months in the absence any antiviral drug treatment. The main obstacle hindering development of this approach for use in humans is anti-drug antibodies, i.e. the development of an antibody response to the delivered antibody that can severely impair the concentrations of delivered antibody that can be achieved. These anti-antibodies are predominantly or exclusively directed to the variable domains, i.e. they are anti-idiotype. This is especially a problem because the mAbs with potent neutralizing activity that we want to deliver for the most part are highly divergent from germline and have unusually long CDR3 regions. We now appear to have found vector design and vector delivery conditions that allow consistent delivery of problematic anti-SIV/anti-HIV mAbs. Nonetheless, continued work is needed to effectively realize the full potential of this approach.
C-104 Defining the glycopeptide epitopes of broadly neutralizing antibodies for HIV vaccine design
Authors: Wang Lai-Xi
Published: April 2018

A major recent progress in HIV vaccine research is the discovery of a class of glycan-reactive broadly neutralizing antibodies (bNAbs) that target conserved N-glycans and peptide segments at the variable (V1V2 and V3) regions. Characterization of the neutralizing epitopes of these bNAbs, represented by PG9 and the PGT series (PGT121-135), constitutes an important step for HIV vaccine design. Mutational and structural studies have played a key role in epitope mapping. However, the glycan specificity and fine epitope structures of these antibodies remain to be characterized in details. Further epitope mapping has been complicated by the tremendous glycosylation heterogeneity of the viral envelope glycoproteins. To address this problem, we have launched a chemical approach that combines synthesis and antibody binding to decipher the glycopeptide neutralizing epitopes. Using a convergent chemoenzymatic synthetic method, we synthesized a series of V1V2 and V3 glycopeptides corresponding to the proposed epitopes of PG9, PGT121, PGT128, and 10-1074. Antibody binding studies with the well-defined glycopeptides enabled new discoveries of the glycan specificity and the requirement of the peptide context in the antigen recognition by these bNAbs. Moreover, a synthetic three-component V3 glycopeptide immunogen carrying a T-helper and a TLR2 ligand was able to raise substantial glycan-dependent antibodies in rabbits. The results will be discussed in the presentation.
D-101 The role of stress agents in immunization against HIV-1 infection and eliciting CD4+ memory stem cells
Authors: Lehner Thomas , Rahman Durdana , Wang Yufei , Wittall Trevor
Published: April 2018

A robust immunological memory is critical for the longevity of any vaccine. We have demonstrated CD4+ T stem cell memory (TSCM) in the Thai RV144 HIV-1 vaccine clinical trial. Comparable TSCM were demonstrated in the mucosal vaccination of women, using HIVgp140-HSP70 conjugate administered by the vaginal route. TSCM can be upregulated by recombinant IL-15 or DC membrane associated IL-15 (maIL-15) by a variety of stress agents, such as thermal, oxidative or ionophore, which we studied in vitro. Recombinant IL-15 elicited >3-fold increase and DC maIL-15 >2-fold increase in CD4+ TSCM. Both systemic and mucosal immunization elicited lower TSCM than the in vitro activated cells. Surprisingly, recall of past exposure to immunogens, such as PPD, showed similar increase to PPD as that to the stress agent. This was shown for CD4 proliferative responses, Th1 cytokines and CC chemokines. As both the homeostatic and inflammasome pathways may be stimulated by stress agents, inhibition studies were carried out to validate this for TSCM. Indeed both pathways may be involved in CD4+ T cell proliferation, though the homeostatic pathway is more significant than the inflammasome one. These studies support the concept that stress agents are important in eliciting and maintaining CD4+ TSCM cell longevity in vaccination.
D-104 Clonal proliferation of CD4 T cells encoding intact HIV-1
Authors: Lichterfeld Mathias
Published: April 2018

HIV-1 causes a chronic, incurable disease due to CD4 T cells that contain replication-competent provirus but exhibit little or no active viral gene expression, and effectively resist combination antiretroviral therapy (cART). Such latently-infected CD4 T cells possess a remarkable long-term stability and typically persist life-long, for reasons that are not fully understood. We have used massive single-genome, near full-length next-generation sequencing of HIV-1 DNA derived from unfractionated PBMC, ex vivo-isolated CD4 T cells, and phenotypically complex memory CD4 T cells from peripheral blood and lymphoid tissues to characterize the dynamics and underlying mechanisms supporting viral persistence. These studies demonstrated multiple sets of independent, near full-length proviral sequences from cART-treated individuals that were completely identical, consistent with clonal expansion of CD4 T cells harboring intact HIV-1. Interestingly, we found that Th1 CD4 T cells, typically responsible for antiviral immune defense, seem to harbor the majority of such clonally-expanded intact proviruses in cells from peripheral blood. In addition, we noted that cells harboring clonally-expanded proviral sequences frequently expressed cell surface markers known to protect CD4 T cells during the vulnerable phase of clonal proliferation, suggesting that HIV-1-infected CD4 T cells rely on physiological mechanisms for maintaining viral reservoir stability through clonal expansion. A closer longitudinal analysis of intact proviruses in distinct CD4 T cell subsets in future studies will be highly informative for developing targeted interventions for viral reservoir manipulation in clinical settings.
D-106 Chromatin Functional States Correlate with the Reversal of Latently HIV-1 Infected Primary CD4+ T cells
Authors: Battivelli Emilie , Dahabieh Matthew S. , Abdel-Mohsen Mohamed , Svensson J. Peter , Da Silva Israel Tojal , Cohn Lilian B. , Gramatica Andrea , Deeks Steven , Greene Warner , Pillai Satish K. , Verdin Eric
Published: April 2018

Current antiretroviral therapies (ART) do not allow for the eradication of the human immunodeficiency virus (HIV) due to the presence of latent proviruses in rare, long-lived resting CD4+ T cells. The main research efforts to eliminate the viral reservoir are focused on the use of latency reversing agents (LRAs) to force the reactivation of the latent provirus, while maintaining ART to prevent de novo infections. Subsequently, reactivation of HIV expression would kill reservoir cells via viral cytopathic effects and/or immune clearance (“shock and kill” strategy). So far, no LRAs tested in clinical trials have succeeded in reducing the reservoir. Furthermore, there is limited understanding as to why some latent proviruses are being induced, while others are not.

We used an improved dual-fluorescent HIV reporter (GKO), which distinguishes productively infected cells from the latent population, to investigate the efficacy of the “shock and kill” strategy. In addition, GKO provides a unique opportunity to (1) explore the impact of HIV integration site specificity on the fate of the infection, and to (2) characterize the inducible subpopulation of latently infected cells, since it allows the isolation of inducible latent and non-inducible latent populations from the productively infected majority.

We first showed that our patients' data was consistent with previously published studies. However, we found that at most 5% of GKO latent proviruses were reactivated. Moreover, the analysis of HIV-1 integration sites from productively, non-inducible and inducible latently infected populations reveals heterogeneity within the latent infections. In contrast to non-inducible latent infections, the integration sites of inducible latent proviruses have similar features to those of productive proviruses, thus demonstrating a prominent role for the site of integration and its chromatin context for the fate of the initial infection as well as for latency reversal.

Our study shows an important roadblock for the “shock and kill” approach to reservoir eradication. Differences between inducible and permanently latent reservoir cells suggest that complete reservoir reactivation and eradication with LRAs may prove impossible, and that a multipronged “functional cure” approach may be necessary.
D-107 HIV Env trimer immunogen design and modification to elicit neutralizing antibodies
Authors: Wyatt Richard
Published: April 2018

A major challenge in HIV-1 vaccine design is to generate antibodies directed toward conserved broadly neutralizing epitopes on the surface-exposed viral envelope glycoprotein (Env). Most conserved epitopes are masked by self N-glycans, limiting naive B cell recognition of the underlying protein surface following Env vaccination or during natural infection. Recently, soluble faithful mimics of the HIV Env spike have been developed, including the stabilized cleavage-independent NFL (native flexibly linked) trimers, but their capacity to elicit broadly cross-reactive tier 2 (clinical isolate) neutralizing responses has so far been limited. The conserved primary receptor, CD4 binding site, is a known neutralizing determinant, but is flanked by self-N-linked glycans, limiting B cell and antibody access to this site. Here, we eliminated up to 4 N-glycans surrounding the CD4 binding site of the NFL trimer without affecting trimer stability or conformation, as demonstrated by multiple biophysical methods and EM. Using these well-ordered trimers, we arrayed them at high density on synthetic liposomal nanoparticles because, as we have shown, this multivalent trimer array enhances B cell activation, germinal center formation and the elicitation of HIV neutralizing antibodies. We performed immunogenicity experiments in animal models, demonstrating that the N-glycan-deleted trimers elicited superior neutralizing responses as a prime for fully glycosylated trimers, compared to multiple immunizations with fully glycosylated trimers alone. The N-glycan deleted priming also resulted in detectable cross-neutralization of a small subset of tier 2-like viruses following boosting. The approach of N-glycan deletion as a prime, coupled with multivalent trimer array, is a promising means to elicit better HIV cross-neutralizing antibodies.
C-106 Pan-neutralizing antibodies derived from human plasma targeting a new epitope
Authors: Sajadi Mohammad M. , Dashti Amir , Pazgier Marzena , Tolbert William D. , Seaman Michael S. , Ouyang Xin , Kim Dongkyoon , Cavet Guy , Redfield Robert R. , Lewis George K. , DeVico Anthony L.
Published: April 2018

Using a new methodology to obtain the sequences of antibodies in circulation, we have discovered a family of antibodies of remarkable breadth and potency: the N49 P series. Some members of this family have the capability to neutralize 100% of isolates tested in a Tier 1-3 multiclade 117 pseudovirus panel, including all pseudovirsuses that were resistant to other mAbs tested in the same panel (PGT121, GT 128, PGT 145, PGDM1400, PGT 151, 10-107 4, 10E8, PG9, PG16, 3BNC117, NIH 45-46, 8ANC195, VRC01, and VRC07). Elisa studies and sequence analysis show the N49 mAbs to have some characteristics of CD4-binding site antibodies. However, crystallographic studies show a bypassing of the CD4-binding site pocket in favor on the inner domain. The N49 P series has potential to be useful in passive immunization and prophylactic vaccine design for HIV-1.
D-111 Influence of age on immune response to influenza vaccination in virologically suppressed HIV infected persons
Authors: Pallikkuth Suresh , deArmas Lesley , Rinaldi Stefano , Georgr Varghese , Pahwa Rajendra , Pahwa Savita
Published: April 2018

Background:

Approximately 5%–20% of the US population contracts influenza infection annually with >200,000 hospitalizations and >35,000 deaths that occur mainly in older adults. We investigated determinants of immune response to influenza vaccine in relation to aging and concurrent HIV infection.

Methods:

154 HIV infected (HIV+) virologically controlled persons on ART and 161 HIV uninfected (HIV−) grouped by age as young (<40 years), middle aged (40–59 years) and old (≥60 years) were given trivalent influenza vaccination. Serological responses to influenza vaccine antigens were correlated with cellular immune activation (IA), plasma markers of inflammation, and immune phenotype and function of peripheral leukocytes, including peripheral T follicular helper cells (pTffh).

Results:

Absolute responders with >4 fold increase in titer to all the vaccine antigens were fewer in HIV+ (14%) than in HIV− (32%), lower in old compared to young, and inversely correlated with age for Ab to H1N1 and B antigen. Several immunologic markers were negative predictors of the vaccine response in HIV infection; these included higher levels of activated pTfh, monocytes expressing inflammatory marker CD11b, activated naive B cells, checkpoint inhibitor Tim3 on CD4 T cells and high plasma sCD25. Positive correlations were found with frequencies of bulk and antigen specific pTfh cells exhibiting high IL-21 and low IL-2 expression and lacking in inflammatory cytokines (TNFa, IL17) production. Although more deficiencies were evident in HIV+ old compared to other groups, the differences between HIV+ and HIV− for Ab responses and immunologic markers were maximal in young age.
E-102 Policy, practice and science in Nigeria: Implementing evidence based research for HIV programming in Nigeria
Authors: Adewole Isaac F.
Published: April 2018

Nigeria with a population of over 180 million currently has a national estimate of 3% prevalence of HIV infection. Briefly, 3 million people are living with HIV; 160,000 pregnant women living with HIV and pediatric HIV infection account for about 30% of global burden. Following the assumption of office by President Muhammadu Buhari in 2015, the country initiated plan and began an aggressive drive in revitalizing the healthcare system towards attainment of Universal Health Coverage in the country.

This presentation will chronicle policies, practices and evidences generated in-country on biology of HIV infection, transmission and management as well other non-orthodox claims of cure. The socio-cultural interpretations, perceptions and behaviours as it affects HIV infection within Nigerian space will be highlighted. The concluding section of the presentation will focus on key priority areas of HIV programming and research that requires international collaborations.
E-104 Virus genomes reveal factors that spread and sustained the Ebola epidemic
Authors: Dudas Gytis
Published: April 2018

The 2013–2016 West African epidemic caused by the Ebola virus was of unprecedented magnitude, duration and impact. Here we reconstruct the dispersal, proliferation and decline of Ebola virus throughout the region by analysing 1,610 Ebola virus genomes, which represent over 5% of the known cases. We test the association of geography, climate and demography with viral movement among administrative regions, inferring a classic “gravity” model, with intense dispersal between larger and closer populations. Despite attenuation of international dispersal after border closures, cross-border transmission had already sown the seeds for an international epidemic, rendering these measures ineffective at curbing the epidemic. We address why the epidemic did not spread into neighbouring countries, showing that these countries were susceptible to substantial outbreaks but at lower risk of introductions. Finally, we reveal that this large epidemic was a heterogeneous and spatially dissociated collection of transmission clusters of varying size, duration and connectivity. These insights will help to inform interventions in future epidemics.
G-103 Regulation of HTLV-1 proviral latency
Authors: Bangham Charles
Published: April 2018

The human leukaemia virus HTLV-1 causes chronic inflammatory disease or an aggressive T-cell malignancy in about 10% of infected people. The risk of these diseases is strongly correlated with the proviral load, which frequently exceeds 10% of peripheral blood mononuclear cells. The high proviral load is limited by a strong, chronically activated host immune response. HTLV-1 does not release cell-free virions, but propagates both within and between hosts by cell-to-cell contact, via the virological synapse.

Until recently, HTLV-1 was thought to be latent in vivo, and persisted chiefly by continuous oligoclonal proliferation of about 100 clones of HTLV-1-infected CD4+ T cells. However, we have shown that a typical individual carries between 104 and 105 clones, and the proviral load–the chief correlate of disease–is determined by the number of clones, not by oligoclonal proliferation. We recently discovered that HTLV-1 alters host chromatin structure in the infected cell, by binding the chromatin architectural protein CTCF, which regulates higher-order chromatin structure and gene expression in vertebrates. Thus, HTLV-1 does a remarkable experiment of nature, by changing the conformation of chromatin in tens of thousands of different ways in each infected host. Two broad questions are raised: first, how does CTCF benefit the virus? Second, how does the change in chromatin structure affect the host? I will show that the abnormal chromatin looping caused by CTCF can deregulate host gene expression and so may act as an oncogenic driver. I will also present evidence that HTLV-1 plus-strand is expressed in intense, intermittent bursts, and that expression minus strand is not, as is currently believed, constitutive.
G-104 The Helicobacter pylori adhesin protein HopQ exploits the dimer interface of human CEACAMs for oncoprotein translocation
Authors: Bonsor Daniel A. , Zhao Qing , Schmidinger Barbara , Weiss Evelyn , Wang Jingheng , Deredge Daniel , Beadenkopf Robert , Dow Blaine , Fischer Wolfgang , Beckett Dorothy , Wintrode Patrick L. , Haas Rainer , Sundberg Eric J.
Published: April 2018

Helicobacter pylori infects half of the world's population and strains that encode the cag type IV secretion system for injection of the oncoprotein CagA into host gastric epithelial cells are associated with elevated levels of cancer. CagA translocation into host cells is dependent on interactions between the H. pylori adhesin protein HopQ and human CEACAMs. Here, we present high-resolution structures of numerous HopQ-CEACAM complexes and CEACAMs in their monomeric and dimeric forms establishing that HopQ uses a coupled folding and binding mechanism to engage the canonical CEACAM dimerization interface for CEACAM recognition. By combining mutagenesis with biophysical and functional analyses, we show that the modes of CEACAM recognition by HopQ and CEACAMs themselves are starkly different. Our data describe precise molecular mechanisms by which microbes exploit host CEACAMs for infection and enable future development of novel oncoprotein translocation inhibitors and H. pylori-specific antimicrobial agents.
G-106 Carcinogenic potential of bacterial biofilms
Authors: Sears Cynthia
Published: April 2018

The colonic microbiome is hypothesized to contribute to the induction and progression of colon cancer. While select bacterial species have been implicated in colon carcinogenesis, recent data also suggest that bacterial community organization and composition are carcinogenic. Studies of paired surgical CRC samples and normal colon mucosa as well as colon biopsies of healthy controls undergoing screening colonoscopy revealed that sporadic colon tumors located proximal to the hepatic flexure are characterized by invasive polymicrobial biofilms that extend to normal colon tissue far distant from the tumor. In contrast, colon mucosal biofilms occur much less frequently in individuals with colon cancer distal to the hepatic flexure and in only about 15% of mucosal samples from healthy colonoscopy controls. This talk will present an update on the intersection of individual microbes, biofilms and mechanisms of colon carcinogenesis. Together our studies support a model by which specific bacteria with their virulence genes as well as microbiota organization act with host immune responses to contribute to colon cancer pathogenesis.
H-104 The HIV pandemic in Sub-Saharan Africa: Challenges, successes and leadership
Authors: Quinn Thomas
Published: April 2018

There are 36.7 million people living with HIV, of whom 19.4 million (53%) live in eastern and southern Africa. Last year, 1.8 million people became newly infected, with 43% residing in eastern and southern Africa. South Africa has over 7 million people infected (20% of the global total), the largest number of infected people in any country. In 2016, 380,000 new infections occurred in South Africa, along with 180,000 AIDS-related deaths. Currently one of every 10 individuals are infected, and in some areas, one of every three young women are infected. By 2005, South Africa had the highest incidence in the world. This led to a vigorous response by the scientific community to study and advocate for a more intensive public health and governmental response. Drs. Quarraisha Abdool and Salim Abdool Karim responded by building the Centre of AIDS Programme of Research in South Africa (CAPRISA), one of the most respected research entities in the continent. They documented very high rates of infection in young women, described social patterns and risk factors of high transmission, identified mucosal factors associated with increased susceptibility, and implemented the first successful trial of Tenofovir microbicide, effective in decreasing acquisition of both HIV and HSV-2 in women. They implemented antiretroviral access programs responsible for a 29% decline in new infections in adults and a 56% decline in neonatal infections since 2010. Their efforts along with others have led to the largest number of people on antiretroviral therapy at 3.5 million people. Drs. Q. and S. Karim have demonstrated the scientific leadership that will be necessary to fully control the HIV pandemic in South Africa.
H-105 Reflections on the impact of nucleotide antiviral drugs
Authors: Martin John
Published: April 2018

Antiviral nucleotide prodrugs have benefitted patients suffering from HIV and viral hepatitis, providing for the possibility to live longer, healthier lives. In addition, tenofovir has allowed for pre-exposure prophylaxis to prevent HIV infection. This is an example of the pioneering work of Salim and Quarraisha Karim.
H-106 Sustained ART-free HIV remission: Obstacles and opportunities
Authors: Fauci Anthony
Published: April 2018

Profound and durable suppression of HIV by antiretroviral therapy (ART) represents a major accomplishment in HIV research. However, HIV persists in patients despite long-term ART therapy and if ART is withdrawn, the virus almost invariably rebounds. Lifelong ART treatment is associated with toxicity, residual chronic inflammation, and the accelerated onset of diseases associated with aging. Therefore, alternatives to lifelong ART are being pursued, with the goal of achieving sustained, ART-free HIV remission. The first pathway to sustained ART-free HIV remission is to completely eradicate the replication-competent HIV reservoir–a classic “cure.” The second pathway is to control HIV rebound without eradication of the virus–referred to as “sustained virologic remission.” Three potential avenues to achieving sustained virologic remission will be discussed. The first approach involves the preservation of natural HIV-specific natural immunity without additional immune enhancements. A key challenge is to determine why the time to HIV rebound following interruption of ART has varied so widely. The second approach involves therapeutic vaccination; in this regard, the results of a recently completed, placebo-controlled therapeutic vaccine trial will be discussed. The third approach is the passive transfer of HIV-specific antibodies. Recent data on the passive transfer of broadly neutralizing anti-HIV antibodies (bNAbs) to individuals whose viremia is suppressed by ART and the effect of these bNAbs in suppressing viral rebound will be presented. In addition, the role of passive transfer of anti-α4β7 antibody in inducing long-term, post-ART remissions in non-human primates will be discussed.
I-102 Probing mechanisms of accelerated coronary atherosclerosis and heart disease in HIV+ people
Authors: Weiss Robert G. , Hays Allison G. , Iantorno Micaela , Bagchi Shashwatee , Gerstenblith Gary
Published: April 2018

Since the advent of effective ART in the 1990's, HIV+ people are living longer and developing chronic diseases including cardiovascular disease that is currently the cause of death in 8%–15% of HIV+ people. HIV+ people have accelerated atherosclerosis and an approximate 50%–70% increase in the risk of myocardial infarction as compared to a comparable, age-matched population. Several factors are thought to contribute to this increased CAD risk including over-representation of traditional risk factors, chronic inflammation, and vascular activation in HIV+ people. However, the importance and interaction of these factors are very poorly understood. This presentation will review the literature on this topic and discuss very recent studies showing that HIV+ people on contemporary ART with viral suppression have severely abnormal coronary endothelial function, a marker of early atherosclerosis and independent predictor of future events, before the development of heart disease. The presentation will review evidence that inflammation may contribute to accelerated atherosclerosis in HIV+ people and discuss new studies investigating contributing mechanisms and potential future therapies for reducing cardiovascular risk in HIV+ people.
I-105 Advances in HCV-associated hepatocellular carcinoma
Authors: Farci Patrizia
Published: April 2018

Over the past two decades, the incidence of HCC has more than tripled in the United States, and this alarming trend is due primarily, if not exclusively, to HCV infection. However, the role of HCV in hepatocarcinogenesis is still unknown. Whether HCV elicits liver cancer indirectly through chronic inflammation and fibrosis, or directly through the expression of viral proteins in a manner analogous to other human oncogenic viruses, remains to be established. In particular, there is limited information on the level of HCV replication within malignant hepatocytes and the molecular interactions between virus and tumor. We found a significant decrease in HCV RNA in the tumor compared to surrounding non-tumorous tissues, whereas no differences were observed in multiple areas of control non-HCC cirrhotic livers. Diminished HCV replication was not associated with changes in miR-122 expression. Tracking of individual variants demonstrated changes in viral population between tumorous and non-tumorous areas, the extent of which correlated with the decline in HCV RNA, suggesting HCV compartmentalization within the tumor. In contrast, compartmentalization was not observed between non-tumorous areas and serum, nor in controls between different areas of the cirrhotic liver or between liver and serum. Our findings indicate that HCV replication within the tumor is restricted, with viral compartmentalization suggesting segregation of specific viral variants in malignant hepatocytes. Our results provide new insights for understanding the role of HCV in HCC and may give new impetus to investigate whether malignant hepatocytes express or more likely have lost expression of factors that restrict viral replication.
I-106 Hepatitis viruses in HIV infection
Authors: Sherman Kenneth
Published: April 2018

Viral hepatitis represents an important comorbidity among those with HIV infection. The epidemiology and pathophysiology is often altered compared to the general population with increased prevalence, increased risk of chronicity, alteration of viral setpoints, and more rapid progression of hepatic fibrosis in many co-infected individuals. Recently, outbreaks of hepatitis A among MSM with HIV have been reported. Hepatitis B infection is often unrecognized and represents an important contributor to morbidity through both liver failure and increased risk of hepatocellular carcinoma. Hepatitis C is also associated with higher rates of chronicity following acute infection, and rapid hepatic fibrosis leading to liver related death. Treatment of HCV is efficacious but must take into account the underlying antiretroviral regimen. Hepatitis D may be more frequent among HBV/HIV infected persons than has been previously recognized, and also represents an independent risk of HCC. Hepatitis E infection can lead to chronic infections in those with HIV and other immunosuppressed states. Standard vaccination practices that are highly effective in the general population to prevent hepatitis A and B are of lower utility among those with HIV and alternative vaccine strategies should be employed.

Conclusion:

Co-infection of hepatitis viruses with HIV leads to alterations in natural history, as well as prevention and treatment strategies. Care providers must be cognizant to these differences in order to provide optimal care for the HIV-infected patient.
I-107 Optimisation of a therapeutic vaccine; the importance of immune modulation
Authors: Dalgleish Angus , Sommerfelt Maja , Sorensen Birger , Smith Peter
Published: April 2018

Vacc-4X is a p24 (gag) peptide based vaccine, shown to reduce viral load (HIVRNA) in HAART interrupted patients, confirmed in a randomised phase II study, which also confirmed vaccination had no effect on the CD4 count. A programme to improve the efficacy of Vacc4X has included peptide modifications to increase uptake by dendritic cells and the breadth of the responses to these peptides.

A recent study (Sorensen B et al, ARHRV 2017) showed that in 3 cohorts of patients, antibodies to the novel heterodimeric construct designed to enhance the immunogenicity of this region containing C5 (501-512) and gp41 (732-44), was associated with slower disease progression and lower viral loads, antibodies to the C5 (501-506) domain correlated with preserved CD4 counts. It is proposed to combine this construct with the Vacc4X to enhance efficacy.

These patient cohorts are all long term infected patients with compromised immune responses, even on HAART. The IMiDs, including Lenalidomide, have been shown to enhance immune responses to cell based vaccines in-vivo and Prevnar in clinical trials. Priming patients with Lenalidomide before Vacc4X led to an increase in CD4 counts in a small randomised study. It is proposed that if Lenalidomide had been given for longer, the effect would have been more significant.

In addition, an immune modulator, M.vaccae, has been shown to reduce the incidence of TB in a randomised study in HIV infected subjects in Africa. M.vaccae and its commercial derivative (IMM-101) have been shown to be ideal adjuvants for anticancer based vaccines. It is proposed that immune modulation by Lenalidomide and IMM-101 could enhance clinical benefit seen with Vacc4X and enhanced responses to C5.
J-102 Decreased levels of seroreactivity in individuals subjected to antiretroviral therapy early in acute HIV infection
Authors: Manak Mark , Shutt Ashley , Eller Leigh , Robb Merlin , Jagodzinski Linda , Ananworanich Jintanat , Peel Sheila
Published: April 2018

WHO guidelines recommend antiretroviral treatment (ART) of all HIV infected individuals regardless of CD4 count. Early treatment minimizes the risk of HIV transmission, lowers the natural reservoir of the virus, and reduces subsequent serious AIDS related events, but may also disrupt emergence of HIV diagnostic markers.

High-risk individuals at early stages of HIV infection, (HIV-1 RNA positive, Western Blot negative or indeterminate), were enrolled into an IRB approved study to examine the outcomes of early HAART initiation. Plasma samples collected at week 0, 2, 12, and 24 were tested by EIA 1/2 Plus O, HIV-1/2 Ag/Ab Combo, HIV-1/2 MultiSpot (MS), and HIV-1 Western Blot (WB) (all from Bio-Rad, Redmond, WA). HIV Viral Load was determined by Abbott m2000 HIV-1 RT PCR (Chicago, IL). Stage of HIV infection was based on the Fiebig staging system.

Of individuals treated at Fiebig I and II, 63.6 and 59.1%, respectively, were antibody negative at 12 weeks. At week 12, MS was reactive in 18.2%, 53.7% and 35.0% of individuals treated at Fiebig I, II, and Fiebig III/IV, and decreased to 9.1%, 48.4% and 30.0%, respectively, by week 24. 52.9% of individuals treated at Fiebig III/IV were negative at week 24. In contrast, all untreated individuals were highly reactive by EIA, WB, MS and RNA by week 2–3 after infection and remained reactive thereafter.

Absence of serological markers in individuals treated early in infection presents challenges in determining status of infection, as some individuals under therapy may test serologically non-reactive and RNA negative, but are infected. These findings may also have implications in monitoring individuals on Pre-exposure Prophylactics (PrEP) by serological tests alone.
J-103 Performance and usability of the OraQuick® HIV Self-test, an oral fluid based HIV self-test, in South Africa
Authors: Reed Michael , Majam Mohammed
Published: April 2018

With 30% of persons living with HIV globally still not knowing their status, increasing access to HIV testing using self-tests is an approach to achieving the United Nations' target goal of diagnosing 90% of all people living with HIV by 2020. The OraQuick HIV Self-Test is an oral fluid based self-test providing results in as little as 20 minutes and is the first self-test to receive WHO Prequalification (July 2017). WHO Prequalification allows access to high quality, easy to use, accurate HIV self-testing in countries wishing to broaden their HIV testing and treatment programs.

This talk describes the results and observations of studies conducted in South Africa to demonstrate ease of use and generation of accurate results in the hands of a lay user. The OraQuick® HIV Self-Test results were compared to results from a fourth Gen EIA with sensitivity of 100% (n=76) and specificity of 99.1% (n=324). A separate comprehension study was conducted to assess lay users' ability to understand information provided on the outer packaging and product insert. Comprehension scores were high 99.5% (n=200) for all critical and safety related concepts. Understanding of the next steps for positive results was 97.5% (n=200) [1].

Many studies have shown and continue to demonstrate that the OraQuick HIV Self-Test is a robust test that provides accurate and reliable results. Incorporating an easy to use oral fluid test into current HIV testing strategies can increase the number of individuals testing, especially those hard to reach high risk populations currently not accessing testing.
J-106 Programmable nucleic acid nanoswitches for the rapid, single-step detection of antibodies in bodily fluids
Authors: Ippodrino Rudy
Published: April 2018

Antibody detection plays a pivotal role in the diagnosis of pathogens and monitoring the success of vaccine immunization. However, current serology techniques require multiple, time-consuming washing and incubation steps, which limit their applicability in point-of-care (POC) diagnostics and high-throughput assays. We developed here a nucleic acid nanoswitch platform able to instantaneously measure Immunoglobulins of type G and E (IgG and IgE) levels directly in blood serum and other bodily fluids. The system couples the advantages of target-binding induced co-localization and nucleic acid conformational-change nanoswitches. Due to the modular nature of the recognition platform the method can potentially be applied to the detection of any antibody for which an antigen can be conjugated to a nucleic acid strand. In this work we show the sensitive, fast and cost-effective detection of 4 different antibodies and demonstrate the possible use of this approach for the monitoring of antibody levels in HIV+ patients immunized with AT20 therapeutic vaccine.
P-A3 Limitations of CD32a expression as a marker of the HIV latent reservoir
Authors: Apps Richard , Bachtel Nathaniel , Huang John , Ren Yanqin , Tovanbutra Sodsai , Phanuphak Nittaya , Kroon Eugene , Ananworanich Jintanat
Published: April 2018

It was recently reported that CD32a accurately marks CD4+ T cells from peripheral blood of ART suppressed people which harbor replication competent HIV. A direct marker of these latently infected cells may be expected to associate with reservoir size, but we find that expression levels of CD32 measured on CD4+ T cells isolated from the blood of 12 ART-suppressed participants did not correlate with measurements of cell-associated DNA or inducible virus in these individuals. We also examined genetic variation in CD32a, characterizing polymorphisms in 93 virally suppressed people on ART. Our analysis of all SNPs observed, including those reported to impact IgG binding and HIV disease progression, found no association of any CD32a variants with levels of HIV provirus. Given these results we attempted to repeat the primary cell sorting experiments described in the original report of CD32 as a marker of latently infected cells. CD4+ T cells with highest CD32 staining were sorted by flow cytometry from peripheral blood of ART suppressed people. These populations were not enriched in viral DNA compared to CD4+CD32- populations, in contrast to the original report. The lack of correlation we observe between variation in CD32 expression or genotype and reservoir size, and failure to replicate isolation of latent cells by sorting of CD4+ T cells based on CD32 staining, indicate CD32 may not be a direct marker of replication competent HIV in CD4+ T cell populations.