Current HIV Research (v.11, #8)

HIV infection is characterized by aberrant B cell responses and B cell dysfunction. These dysfunctionalresponses have been extensively documented in peripheral blood and organized lymphoid tissues such as the lymphnodes. Though the loss of CD4 T cell help has been thought to play a key role in dysfunctional B cell responses, recentstudies have implicated a subset of CD4 T helper cells called the T follicular helper (Tfh) cells in this process. Tfh cellsinteract with B cells and play a key role in mediating the germinal center reaction, and driving the differentiation andmaturation of B cells. Why Tfh expands in some HIV infected individuals as compared to their loss in others is still notclear. Here we review some of the recent developments in the field and discuss the implications of Tfh cell dysregulationon B cell responses during HIV infection.

Acquired Immunodeficiency Syndrome (AIDS) was discovered 30 years ago and was followed by theidentification and characterization of its causative agent, Human Immunodeficiency Virus (HIV). Increasing spread ofretroviral infections has impelled science to understand the evolution of retroviruses from primates to humans. In thecourse of evolution, host cells have developed intracellular proteins to counteract the transforming viral defence system.Such inhibitory endogenous intracellular proteins are known as restriction factors. Tripartite motif protein isoform 5 alpha(TRIM5α), Apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC), and Tetherin proteins are fewimportant restriction factors that have been extensively studied. Several evidences have conveyed information regardingspecific adaptations occurring in HIV-1 and its relatives to inhibit these host defenses; making the study more interesting.The characteristic potential of restriction factors to restrict the replication of retroviruses was enticing when studies werefound that HIV-1 virus cannot infect nonhuman primate species. This review emphasizes on TRIM5α as a restrictionfactor and its significance in the evolution of retroviruses. It also accentuates the role of polymorphism within the regionsof TRIM5α in both human and primate species that eventually affect the cross-species transmission of immunodeficiencyviruses.

Antigen-presenting viral vectors have been extensively used as vehicles for the presentation of antigens to theimmune system in numerous vaccine strategies. Particularly in HIV vaccine development efforts, two main viral vectorshave been used as antigen carriers: (a) live attenuated vectors and (b) virus-like particles (VLPs); the former, althoughhighly effective in animal studies, cannot be clinically tested in humans due to safety concerns and the latter have failed toinduce broadly neutralizing anti-HIV antibodies. For more than two decades, Inoviruses (non-lytic bacterial phages) havealso been utilized as antigen carriers in several vaccine studies. Inoviral vectors are important antigen-carriers in vaccinedevelopment due to their ability to present an antigen on their outer architecture in many copies and to their natural highimmunogenicity. Numerous fundamental studies have been conducted, which have established the unique properties ofantigen-displayed inoviral vectors in HIV vaccine efforts. The recent isolation of new, potent anti-HIV broadlyneutralizing monoclonal antibodies provides a new momentum in this emerging technology.

HIV-1 Rev Multimerization: Mechanism and Insights by Thomas Vercruysse, Dirk Daelemans (623-634).
To export intron-containing viral mRNAs that encode the structural components of new viral particles from thenucleus to the cytoplasm, HIV-1 uses the cellular CRM1 export pathway that is exploited by the viral Rev protein. Revmultimerizes on the Rev response element (RRE) present in the intron-containing RNA species to bridge these to thecellular export factor CRM1. As a result, this Rev-RRE complex is exported to the cytoplasm. This review provides asystematic overview of different aspects of the crucial function of Rev multimerization, such as co-operative Rev-Rev andRev-RNA interactions, the biological function of Rev multimerization, the relevance of Rev multimerization in theabsence of RRE and its potential as a therapeutic target.

Genotypic and Phenotypic Comparison of Enteroaggregative Escherichia coli Isolates from HIV-Positive and Non-HIV Diarrheal Samples by Anis Jafari, Ebrahim Shafaei, Mana Oloomi, Mohammad-Reza Aghasadeghi, Saeid Bouzari (635-641).
Enteroaggregative Escherichia coli (EAEC) have been isolated from both HIV-positive and non-HIV diarrhealsamples. In this study a collection of 18 isolates from these two groups were compared for biofilm formation andantibiotic resistance and for the presence of 14 virulence-related genes. All the HIV-positive and over 66% of the non-HIV strains were PCR-negative for adhesion-related sequences indicating that as yet unknown adhesins may play a role.However, despite some variations, the prevalence rate of the virulence-related genes was not significantly different in thetwo groups. HIV-positive isolates were biofilm producer but only a single weak biofilm former was observed among thenon-HIV strains. The rate of resistance to most of the antibiotics used was higher among the HIV-positive group than thenon-HIV isolates, but was significantly higher for amoxicillin-calvulanic acid (100%) and nalidixic acid (55.5%). Pulsefield gel electrophoresis of the isolates produced 17 unique profiles reflecting the exiting heterogeneity of the isolates.

Evaluation of Boosted and Unboosted Atazanavir Plasma Concentration in HIV Infected Patients by Silvia Amadasi, Silvia Odolini, Emanuele Foca, Annafranca Panzali, Carlo Cerini, Lucia Lonati, Maria C. Pezzoli, Paola Nasta, Salvatore Casari, Francesco Castelli, Eugenia Quiros-Roldan (642-646).
Objectives: The aim of the study was to identify variables that can influence atazanavir plasma concentration.;Methods: We retrospectively analysed atazanavir trough concentration of HIV infected patients who performedtherapeutic drug monitoring between October 2007 and July 2011. Qualitative variables were compared with X2 test whilecontinuous ones with Mann-Whitney and Student's t-test. A linear regression model was used to investigate factorsinfluencing atazanavir plasma concentration. Therefore, we analysed the impact of cirrhosis on atazanavirpharmacokinetic variability.;Results: 255 plasma samples from 179 patients were analysed. At the univariate analysis female gender (+144.4 ng/mL;p=0.05) and tenofovir (+196.8 ng/mL; p=0.002) were associated with higher atazanavir concentrations. The multivariatemodel confirmed these two variables (+164.6 ng/mL; p=0.02 and +150.4 ng/mL; p=0.01) as independently associatedwith higher atazanavir trough concentration. The analysis of cirrhotic population showed an influence of tenofovir (-255.9ng/mL; p=0.01), increased AST (+95.3 ng/mL; p=0.09), ALT (+67.9 ng/mL; p=0.07) and creatinine (+517.2 ng/mL;p=0.04). The multivariate model confirm that tenofovir was associated with lower atazanavir trough concentration (-284.1ng/mL; p=0.005) while AST values significantly increased atazanavir concentrations (+114.5 ng/mL; p=0.03).;Discussion: Atazanavir is a safe and manageable drug. Our results suggest that female patients tend to have higheratazanavir plasma concentration, while the effect of tenofovir needs to be better clarified.

Detection of Cryptococcus neoformans Capsular Antigen in HIV-Infected Patients in the State of Para in the North of Brazil by Maurimelia M. da Costa, Lucimar di Paula Madeira, Rosimar N.M. Feitosa, Marluísa de Oliveira G. Ishak, Ricardo Ishak, Silvia H.M. da Silva, Antonio C.R. Vallinoto (647-651).
Cryptococcus neoformans is an important cause of morbidity in HIV-infected patients worldwide. In thenorthern region of Brazil, the prevalence of this infection is poorly known due to a lack of systematic investigations. Thisstudy aimed to determine the occurrence of cryptococcosis by detecting antigenaemia in HIV-infected patients in the Stateof Para, Brazil. A latex Cryptococcus antigen detection kit was used to test 418 serum samples from HIV-infected patientsseen at two Infectious Disease Specialized Units in the State of Para. The C. neoformans antigenaemia prevalence was2.6%, and titres reached 1:8. The cases occurred mainly in asymptomatic females, and 45% presented CD4+ T lymphocytecounts of fewer than 200 cells/mm3. These results show the importance of early C. neoformans antigenaemia detection toprevent fungal disease.

Progress in Prevention of Mother-to-Child Transmission of HIV-1 in Zhejiang Province, China, 2007-2013 by Xiao-Hui Zhang, Wei Lu, Qiong-Yan Wu, Jing-Yi Jiang, Dan-Qing Chen, Li-Qian Qiu (652-657).
This is a retrospective study based on surveillance of Human Immunodeficiency Virus type-1 (HIV-1) positivepregnant women and their children in China's Zhejiang Province. HIV counseling and testing, mother and infantcharacteristics, and outcomes are reported here.;This study compares two principal periods, the period from 2007-2009 and the period from 2010 to 2013. The averagerate of HIV counseling among pregnant women rose from 84.87% during the earlier period to 99.08% during the latterperiod. And the rate of HIV testing also rose significantly, from 80.60% to 98.58%. The HIV-1 prevalence amongpregnant women increased slightly, from 0.01% to 0.02%. Over 70% of infected women were migrants. Half of theseHIV-1 positive pregnant women were 20-30 years old. Significant differences in the characteristics of HIV-1 positivepregnant women were observed with time. The proportion of women who were employed increased dramatically from anaverage of 15.03% during 2007-2009 to an average of 31.34% during 2010-2013 and the proportion of women who hadcompleted high school education increased from 0.52% to 6.51%. During 2007-2009, an average of 3.11% of thesewomen was diagnosed before their pregnancies. During 2010-2013, this average reached to 32.53%. Sexual contactremained the primary route of transmission route during both periods, accounting for half of the infections. The proportionof women who had acquired HIV by blood transfusion declined noticeably. The proportion of mothers and children withantiretroviral therapy increased considerably over time. The overall mother-to-child transmission rate was found to be7.14%.;Although some progress has been made, further work should be performed, fostering early identification and timelytherapy. Particular attention should be paid to health care of migrants.