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1. Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006–2011)

Author

Sheila N. Balinda, Anne Kapaata, Rui Xu, Maria G. Salazar, Allison T. Mezzell, Qianhong Qin, Kimberly Herard, Dario Dilernia, Anatoli Kamali, Eugene Ruzagira, Freddie M. Kibengo, Heeyah Song, Christina Ochsenbauer, Jesus F. Salazar-Gonzalez, Jill Gilmour, Eric Hunter, Ling Yue, and Pontiano Kaleebu

Subjects
HIV-1, subtype D, recombinant, T/F, Microbiology, QR1-502
Abstract

Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5′ and 3′ half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the gag/pol region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses (n = 3) and inter-subtype mosaic recombinants (n = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies.

Published
2022
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2. Conserved signatures indicate HIV-1 transmission is under strong selection and thus is not a "stochastic" process.

Author

Gonzalez, Mileidy, DeVico, Anthony L., and Spouge, John L.

Subjects
*HIV infection transmission, *PHENOTYPES, *GENOTYPES, *STOCHASTIC processes, *RETROVIRUS diseases
Abstract

Recently, Oberle et al. published a paper in Retrovirology evaluating the question of whether selection plays a role in HIV transmission. The Oberle study found no obvious genotypic or phenotypic differences between donors and recipients of epidemiologically linked pairs from the Swiss cohort. Thus, Oberle et al. characterized HIV-1 B transmission as largely "stochastic", an imprecise and potentially misleading term. Here, we re-analyzed their data and placed them in the context of transmission data for over 20 other human and animal trials. The present study finds that the transmitted/founder (T/F) viruses from the Swiss cohort show the same non-random genetic signatures conserved in 118 HIV-1, 40 SHIV, and 12 SIV T/F viruses previously published by two independent groups. We provide alternative interpretations of the Swiss cohort data and conclude that the sequences of their donor viruses lacked variability at the specific sites where other studies were able to demonstrate genotypic selection. Oberle et al. observed no phenotypic selection in vitro, so the problem of determining the in vivo phenotypic mechanisms that cause genotypic selection in HIV remains open. [ABSTRACT FROM AUTHOR]

Published
2017
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3. Characterization of Near Full-Length Transmitted/Founder HIV-1 Subtype D and A/D Recombinant Genomes in a Heterosexual Ugandan Population (2006–2011).

Author

Balinda, Sheila N., Kapaata, Anne, Xu, Rui, Salazar, Maria G., Mezzell, Allison T., Qin, Qianhong, Herard, Kimberly, Dilernia, Dario, Kamali, Anatoli, Ruzagira, Eugene, Kibengo, Freddie M., Song, Heeyah, Ochsenbauer, Christina, Salazar-Gonzalez, Jesus F., Gilmour, Jill, Hunter, Eric, Yue, Ling, and Kaleebu, Pontiano

Subjects
*HIV, *MOLECULAR cloning, *VIRAL genomes, *VIRAL replication, *T cells
Abstract

Detailed characterization of transmitted HIV-1 variants in Uganda is fundamentally important to inform vaccine design, yet studies on the transmitted full-length strains of subtype D viruses are limited. Here, we amplified single genomes and characterized viruses, some of which were previously classified as subtype D by sub-genomic pol sequencing that were transmitted in Uganda between December 2006 to June 2011. Analysis of 5′ and 3′ half genome sequences showed 73% (19/26) of infections involved single virus transmissions, whereas 27% (7/26) of infections involved multiple variant transmissions based on predictions of a model of random virus evolution. Subtype analysis of inferred transmitted/founder viruses showed a high transmission rate of inter-subtype recombinants (69%, 20/29) involving mainly A1/D, while pure subtype D variants accounted for one-third of infections (31%, 9/29). Recombination patterns included a predominance of subtype D in the gag/pol region and a highly recombinogenic envelope gene. The signal peptide-C1 region and gp41 transmembrane domain (Tat2/Rev2 flanking region) were hotspots for A1/D recombination events. Analysis of a panel of 14 transmitted/founder molecular clones showed no difference in replication capacity between subtype D viruses (n = 3) and inter-subtype mosaic recombinants (n = 11). However, individuals infected with high replication capacity viruses had a faster CD4 T cell loss. The high transmission rate of unique inter-subtype recombinants is striking and emphasizes the extraordinary challenge for vaccine design and, in particular, for the highly variable and recombinogenic envelope gene, which is targeted by rational designs aimed to elicit broadly neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
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4. HIV-Specific B Cell Frequency Correlates with Neutralization Breadth in Patients Naturally Controlling HIV-Infection

Author

Rouers, Angeline, Klingler, Jéromine, Su, Bin, Samri, Assia, Laumond, Géraldine, Even, Sophie, Avettand-Fenoel, Véronique, Richetta, Clemence, Paul, Nicodème, Boufassa, Faroudy, Hocqueloux, Laurent, Mouquet, Hugo, Rouzioux, Christine, Lambotte, Olivier, Autran, Brigitte, Graff-Dubois, Stéphanie, Moog, Christiane, Moris, Arnaud, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Casrouge, Armanda, Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Capital University of Medical Sciences [Beijing] (CUMS), Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital La Source [Orléans] (HLSO), Réponse humorale aux pathogènes, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des Maladies Virales et Autoimmunes (IMVA - U1184), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Infectious Diseases Models for Innovative Therapies (IDMIT), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Hôpitaux Universitaires Paris Sud [AP-HP] (HUPS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and This work was granted by the ANRS (Agence nationale de recherches sur le SIDA et les hépatites virales). We thank the Dormeur Foundation, Vaduz, for providing AID ELISPOT Reader.

Subjects
immunoglobulin G (n)Ab, [SDV]Life Sciences [q-bio], intermediate memory B cells MZ-like B cells, lcsh:Medicine, HIV Infections, antibody secreting cell AM, RM, resting memory B cells, TLM B cells, tissue like memory B cells, immunoglobulin G, ADCC, antibody-dependent cell-mediated cytotoxicity, activated memory B cells RM, cART, combined antiretroviral therapy, marginal zone-like B cells, transmitted/founder virus PBMC, marginal zone-like B cells TLM B cells, TLM B cells, B-Lymphocytes, lcsh:R5-920, antibody secreting cell, human immunodeficiency virus, B cell-ELISPOT, virus diseases, tissue like memory B cells, peripheral blood mononuclear cells, HIV Elite controllers Memory B cells B cell-ELISPOT Neutralization Tier-2 virus IgG HIV, transmitted/founder virus, Env, HIV envelope protein, HIV, human immunodeficiency virus, [SDV] Life Sciences [q-bio], PBMC, peripheral blood mononuclear cells, ASC, antibody secreting cell, (neutralizing) antibody, lcsh:Medicine (General), ADCC, resting memory B cells IM, Research Paper, Env, RM, T/F, transmitted/founder virus, IgG, MZ-like B cells, marginal zone-like B cells, T/F, IgG, immunoglobulin G, combined antiretroviral therapy, cART, CTL, cytotoxic T cell, antibody-dependent cell-mediated cytotoxicity, activated memory B cells, peripheral blood mononuclear cells ASC, ASC, cytotoxic T cell T/F, Neutralization, (neutralizing) antibody ADCC, human immunodeficiency virus Env, (n)Ab, (neutralizing) antibody, Humans, Alleles, intermediate memory B cells, elite controller IgG, EC, resting memory B cells, EC, elite controller, AM, activated memory B cells, antibody-dependent cell-mediated cytotoxicity CTL, lcsh:R, PBMC, elite controller, HIV, combined antiretroviral therapy EC, IM, Memory B cells, HIV envelope protein, (n)Ab, AM, IM, intermediate memory B cells, Elite controllers, HLA-B Antigens, CTL, Tier-2 virus, HIV envelope protein cART, MZ-like B cells, cytotoxic T cell
Abstract

HIV-specific broadly neutralizing antibodies (bnAbs) have been isolated from patients with high viremia but also from HIV controllers that repress HIV-1 replication. In these elite controllers (ECs), multiple parameters contribute to viral suppression, including genetic factors and immune responses. Defining the immune correlates associated with the generation of bnAbs may help in designing efficient immunotherapies. In this study, in ECs either positive or negative for the HLA-B*57 protective allele, in treated HIV-infected and HIV-negative individuals, we characterized memory B cell compartments and HIV-specific memory B cells responses using flow cytometry and ELISPOT. ECs preserved their memory B cell compartments and in contrast to treated patients, maintained detectable HIV-specific memory B cell responses. All ECs presented IgG1 + HIV-specific memory B cells but some individuals also preserved IgG2 + or IgG3 + responses. Importantly, we also analyzed the capacity of sera from ECs to neutralize a panel of HIV strains including transmitted/founder virus. 29% and 21% of HLA-B*57 + and HLA-B*57 − ECs, respectively, neutralized at least 40% of the viral strains tested. Remarkably, in HLA-B*57 + ECs the frequency of HIV-Env-specific memory B cells correlated positively with the neutralization breadth suggesting that preservation of HIV-specific memory B cells might contribute to the neutralizing responses in these patients., Highlights • In contrast to treated HIV-infected patients, elite controllers (ECs) maintain HIV-specific memory B cell responses. • In HLA-B*57 + ECs, HIV-specific B cell frequency correlates positively with the neutralization breadth of tier-2 HIV strains. • In HLA-B*57 + and HLA-B*57 − ECs different antibody functions are probably involved in suppressing HIV replication. A fraction of HIV-1-infected individuals (so-called elite controllers, ECs) naturally control HIV-1 replication maintaining undetectable viral loads. Understanding the mechanisms implicated in natural control of HIV-1 infection will help in developing efficient HIV vaccines. In ECs, we analyzed the influence of B cell antibody responses. We show that in contrast to successfully treated HIV-1-infected patients, ECs preserve memory B cell compartments and maintain HIV-specific B cell responses. In ECs positive for the protective HLA-B*57 allele, HIV-specific memory B cell responses are positively associated with the breadth of HIV neutralization. These findings will help develop novel immunotherapies to fight HIV.

Published
2017

5. Conserved signatures indicate HIV-1 transmission is under strong selection and thus is not a 'stochastic' process

Author

Mileidy Gonzalez, Anthony L. DeVico, and John L. Spouge

Subjects
0301 basic medicine, T/F, Selection during HIV transmission, HIV Infections, Context (language use), Biology, law.invention, 03 medical and health sciences, law, Virology, Correspondence, Genotype, Transmitted/founder virus, Humans, Phenotypic versus genotypic selection, Selection (genetic algorithm), Genetics, Stochastic Processes, Transmission signatures, Retrovirology, Phenotype, 030104 developmental biology, Infectious Diseases, Transmission (mechanics), Hiv 1 transmission, Cohort, HIV-1
Abstract

Recently, Oberle et al. published a paper in Retrovirology evaluating the question of whether selection plays a role in HIV transmission. The Oberle study found no obvious genotypic or phenotypic differences between donors and recipients of epidemiologically linked pairs from the Swiss cohort. Thus, Oberle et al. characterized HIV-1 B transmission as largely “stochastic”, an imprecise and potentially misleading term. Here, we re-analyzed their data and placed them in the context of transmission data for over 20 other human and animal trials. The present study finds that the transmitted/founder (T/F) viruses from the Swiss cohort show the same non-random genetic signatures conserved in 118 HIV-1, 40 SHIV, and 12 SIV T/F viruses previously published by two independent groups. We provide alternative interpretations of the Swiss cohort data and conclude that the sequences of their donor viruses lacked variability at the specific sites where other studies were able to demonstrate genotypic selection. Oberle et al. observed no phenotypic selection in vitro, so the problem of determining the in vivo phenotypic mechanisms that cause genotypic selection in HIV remains open.

Published
2017

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