Human Non-neutralizing HIV-1 Envelope Monoclonal Antibodies Limit the Number of Founder Viruses during SHIV Mucosal Infection in Rhesus Macaques

Santra, Sampa,Tomaras, Georgia D.,Warrier, Ranjit,Nicely, Nathan I.,Liao, Hua-Xin,Pollara, Justin,Liu, Pinghuang,Alam, S. Munir,Zhang, Ruijun,Cocklin, Sarah L.,Shen, Xiaoying,Duffy, Ryan,Xia, Shi-Mao Public Library of Science 2015 PLoS pathogens Vol.11 No.8

<▼1><P>HIV-1 mucosal transmission begins with virus or virus-infected cells moving through mucus across mucosal epithelium to infect CD4<SUP>+</SUP> T cells. Although broadly neutralizing antibodies (bnAbs) are the type of HIV-1 antibodies that are most likely protective, they are not induced with current vaccine candidates. In contrast, antibodies that do not neutralize primary HIV-1 strains in the TZM-bl infection assay are readily induced by current vaccine candidates and have also been implicated as secondary correlates of decreased HIV-1 risk in the RV144 vaccine efficacy trial. Here, we have studied the capacity of anti-Env monoclonal antibodies (mAbs) against either the immunodominant region of gp41 (7B2 IgG1), the first constant region of gp120 (A32 IgG1), or the third variable loop (V3) of gp120 (CH22 IgG1) to modulate <I>in vivo</I> rectal mucosal transmission of a high-dose simian-human immunodeficiency virus (SHIV-BaL) in rhesus macaques. 7B2 IgG1 or A32 IgG1, each containing mutations to enhance Fc function, was administered passively to rhesus macaques but afforded no protection against productive clinical infection while the positive control antibody CH22 IgG1 prevented infection in 4 of 6 animals. Enumeration of transmitted/founder (T/F) viruses revealed that passive infusion of each of the three antibodies significantly reduced the number of T/F genomes. Thus, some antibodies that bind HIV-1 Env but fail to neutralize virus in traditional neutralization assays may limit the number of T/F viruses involved in transmission without leading to enhancement of viral infection. For one of these mAbs, gp41 mAb 7B2, we provide the first co-crystal structure in complex with a common cyclical loop motif demonstrated to be critical for infection by other retroviruses.</P></▼1><▼2><P><B>Author Summary</B></P><P>Antibodies specifically recognize antigenic sites on pathogens and can mediate multiple antiviral functions through engagement of effector cells via their Fc region. Current HIV-1 vaccine candidates induce polyclonal antibody responses with multiple antiviral functions, but do not induce broadly neutralizing antibodies. An improved understanding of whether certain types of non-neutralizing HIV-1 specific antibodies can individually protect against HIV-1 infection may facilitate vaccine development. Here, we test whether non-neutralizing antibodies with multiple antiviral functions mediated through FcR engagement and recognition of virus particles or virus-infected cells can limit infection, despite lacking classical virus neutralization activity. In a passive antibody infusion-rhesus macaque challenge model, we tested the ability of non-neutralizing monoclonal antibodies to limit virus acquisition. We demonstrate that two different types of non-neutralizing antibodies, one that recognizes both virus particles and infected cells (7B2) and another that recognizes only infected cells (A32) were capable of decreasing the number of transmitted founder viruses. Further, we provide the structure of 7B2 in complex with the gp41 cyclical loop motif, a motif critical for entry. These findings provide insights into the role that antibodies with antiviral properties, including virion capture and FcR mediated effector function, may play in protecting against HIV-1 acquisition.</P></▼2>

The Influence of Iron on<i>Pseudomonas aeruginosa</i>Physiology : <i>A REGULATORY LINK BETWEEN IRON AND QUORUM SENSING</i>

Oglesby, Amanda G.,Farrow III, John M.,Lee, Joon-Hee,Tomaras, Andrew P.,Greenberg, E. P.,Pesci, Everett C.,Vasil, Michael L. American Society for Biochemistry and Molecular Bi 2008 The Journal of biological chemistry Vol.283 No.23

<P>In iron-replete environments, the Pseudomonas aeruginosa Fur (ferric uptake regulator) protein represses expression of two small regulatory RNAs encoded by prrF1 and prrF2. Here we describe the effects of iron and PrrF regulation on P. aeruginosa physiology. We show that PrrF represses genes encoding enzymes for the degradation of anthranilate (i.e. antABC), a precursor of the Pseudomonas quinolone signal (PQS). Under iron-limiting conditions, PQS production was greatly decreased in a DeltaprrF1,2 mutant as compared with wild type. The addition of anthranilate to the growth medium restored PQS production to the DeltaprrF1,2 mutant, indicating that its defect in PQS production is a consequence of anthranilate degradation. PA2511 was shown to encode an anthranilate-dependent activator of the ant genes and was subsequently renamed antR. AntR was not required for regulation of antA by PrrF but was required for optimal iron activation of antA. Furthermore, iron was capable of activating both antA and antR in a DeltaprrF1,2 mutant, indicating the presence of two distinct yet overlapping pathways for iron activation of antA (AntR-dependent and PrrF-dependent). Additionally, several quorum-sensing regulators, including PqsR, influenced antA expression, demonstrating that regulation of anthranilate metabolism is intimately woven into the quorum-sensing network of P. aeruginosa. Overall, our data illustrate the extensive control that both iron regulation and quorum sensing exercise in basic cellular physiology, underlining how intermediary metabolism can affect the regulation of virulence factors in P. aeruginosa.</P>

Predictors of durable immune responses six months after the last vaccination in preventive HIV vaccine trials

Huang, Yunda,Zhang, Lily,Janes, Holly,Frahm, Nicole,Isaacs, Abby,Kim, Jerome H.,Montefiori, David,McElrath, M. Julie,Tomaras, Georgia D.,Gilbert, Peter B. Elsevier 2017 Vaccine Vol.35 No.8

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>The evaluation of durable immune responses is important in HIV vaccine research and development. The efficiency of such evaluation could be increased by incorporating predictors of the responses in the statistical analysis. In this paper, we investigated whether and how baseline demographic variables and immune responses measured two weeks after vaccination predicted durable immune responses measured six months later.</P> <P><B>Methods</B></P> <P>We included data from seven preventive HIV vaccine regimens evaluated in three clinical trials: a Phase 1 study of four DNA, NYVAC and/or AIDSVAX vaccine regimens (HVTN096), a Phase 2 study of two DNA and/or MVA vaccine regimens (HVTN205), and a Phase 3 study of a single ALVAC/AIDSVAX regimen (RV144). Regularized random forests and linear regression models were used to identify and evaluate predictors of the positivity and magnitude of durable immune responses.</P> <P><B>Results</B></P> <P>We analyzed 201 vaccine recipients with data from 10 to 127 immune response biomarkers, and 3–5 demographic variables. The best prediction of participants’ durable response positivity based on two-week responses rendered up to close-to-perfect accuracy; the best prediction of participants’ durable response magnitude rendered correlation coefficients between the observed and predicted responses ranging up to 0.91. Though prediction performances differed among biomarkers, durable immune responses were best predicted by the two-week response level of the same biomarker. Adding demographic information and two-week response levels of different biomarkers provided little or no improvement in the predictions.</P> <P><B>Conclusions</B></P> <P>For some biomarkers and for the vaccines we studied, two-week post-vaccination responses can well predict durable responses six months later. Therefore, if immune response durability is only assessed in a sub-sample of vaccine recipients, statistical analyses of durable responses will have increased efficiency by incorporating two-week response data. Further research is needed to generalize the findings to other vaccine regimens and biomarkers.</P> <P>Clinicaltrials.gov identifiers: NCT01799954, NCT00820846, NCT00223080.</P> <P><B>Highlights</B></P> <P> <UL> <LI> HIV vaccine-induced immune responses at 2weeks predict those 6months later. </LI> <LI> The former responses can increase evaluation efficiency of vaccine durability. </LI> <LI> The former responses of the same biomarker best predict the latter. </LI> <LI> Demographics and responses of other biomarkers add little for prediction. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Adjuvant-dependent innate and adaptive immune signatures of risk of SIV_mac251 acquisition

Vaccari, Monica,Gordon, Shari N,Fourati, Slim,Schifanella, Luca,Liyanage, Namal P M,Cameron, Mark,Keele, Brandon F,Shen, Xiaoying,Tomaras, Georgia D,Billings, Erik,Rao, Mangala,Chung, Amy W,Dowell, Ka Nature Publishing Group 2016 Nature medicine Vol.22 No.7

<P>A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum. decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution, of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.</P>